Ester compound and medicinal use thereof

ABSTRACT

A novel therapeutic agent for hyperlipidemia, which is an ester compound represented by the formula (1″) 
                         
(wherein
         R 1  and R 2  are each hydrogen atom or optionally substituted aryl, etc.;   X is —COO— or —CON(R 10 )—;   R 3  and R 4  are each hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, etc.;   R 5 , R 6  and R 7  are each hydrogen atom, C 1 -C 6  alkyl or C 1 -C 6  alkoxy, etc.;   R 8  and R 9  are each independently hydrogen atom, C 1 -C 6 alkyl, —CON(R 18 )(R 19 ) or —COO(R 20 ), etc.;   ring A, ring B and ring C are each independently aryl or heterocycle residue, etc.;   Alk 1  and Alk 2  are each independently alkanediyl, etc.;   l and m are each an integer of 0 or 1 to 3) or a prodrug thereof, or a pharmaceutically acceptable salt of either.       
     The therapeutic agent selectively inhibits MTP in the small intestine, thus causes no such side effect as a fatty liver.

This application is a US national stage application of PCT applicationPCT/JP03/02398 filed on Feb. 28, 2003, and claims benefit of priority ofJapan Application No.: JP2002-53876, filed Feb. 28, 2002, the contentsof which are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel ester compound, and alsorelates to a pharmaceutical composition comprising a novel estercompound which selectively inhibits microsomal triglyceride transferprotein (MTP) in the small intestine or a prodrug thereof, or apharmaceutically acceptable salt of either. Further, the presentinvention relates to an agent for the treatment or prophylaxis ofhyperlipidemia, arteriosclerosis, coronary artery diseases, obesity,diabetes or hypertension comprising a novel ester compound whichselectively inhibits MTP in the small intestine or a prodrug thereof, ora pharmaceutically acceptable salt of either as an active ingredient. Inaddition, the present invention relates to an agent for the treatment orprophylaxis of hyperlipidemia, arteriosclerosis, coronary arterydiseases, obesity, diabetes or hypertension, which has a novel functionthat has never been known before.

BACKGROUND ART

It has been said that hyperlipidemia, diabetes, hypertension or the likeis one of the risk factors for arteriosclerosis. Hyperlipidemia is acondition where the concentration of lipid such as cholesterol isabnormally elevated in the blood. Types of hyperlipidemia, depending onthe cause, include primary hyperlipidemia caused by genetic abnormalityin enzyme, protein, lipoprotein and the like which participate in themetabolism of low-density lipoprotein (LDL), secondary hyperlipidemiadue to various disease or drug administration, and acquiredhyperlipidemia basically resulting from overnutrition.

Meanwhile, lipid taken in from food is absorbed in the small intestineby the action of bile acid, and secreted as chylomicron in the blood vialymphatic vessels. The triglyceride moiety of the secreted chylomicronsis hydrolyzed to free fatty acids by the action of lipoprotein lipase(LPL) existing in capillary vessels to become chylomicron remnantshaving a high content of cholesteryl ester (CE), which is then absorbedin the liver by the mediation of chylomicron remnant receptor in theliver. Further, in the liver, the absorbed chylomicron remnant and freefatty acid are converted to CE and TG, respectively, which are thenassociated with apolipoprotein B synthesized on rough surfacedendoplasmic reticulum to form very low density lipoprotein (VLDL). TheVLDL is transferred to the Golgi apparatus, modified and secretedoutside cells, and it becomes intermediate density lipoprotein (IDL) bythe action of LPL. The IDL is converted to LDL by the action of hepatictriglyceride lipase (HTGL), and lipids are distributed to peripheraltissues.

It has long been indicated that, during the above-mentioned formation ofchylomicron in the small intestine or VLDL in the liver, a proteinhaving TG- or CE-transfer activity is existing in microsomal fractionsof the small intestine or liver. Meanwhile, the protein, i.e. MTP(microsomal triglyceride transfer protein) was purified and separatedfrom microsomal fractions of bovine liver by Wetterau et al. in 1985(Wetterau J. R. et al: Chem. Phys. Lipids 38, 205-222(1985)). MTP,however, began attracting a lot of attention in the field of clinicalmedicine only after it was reported in 1993 that the cause ofabetalipoproteinemia lay in the deficit of MTP. In other word, thedisease is characterized in that, while the genes related toapolipoprotein B are normal, apolipoprotein B is hardly detected in theserum, the level of serum cholesterol is 50 mg/dL or lower, the level ofserum triglyceride is extremely low and, moreover, lipoproteinsincluding apolipoprotein B such as chylomicron, VLDL, LDL, etc. do notat all exist in the blood. By this finding, it has been shown that MTPis an integral protein involved in the association betweenapolipoprotein B and TG or CE, i.e. the formation of VLDL orchylomicron, and plays an essential role in secretion thereof.

Since lipid is by nature insoluble in water, lipid in the blood iscombined with a hydrophilic protein known as apolipoprotein and existsas so-called lipoprotein. All the VLDL, IDL, LDL or chylomicron, etc.related to hyperlipidemia are a lipoprotein.

MTP exists in the microsome fractions of hepatocytes and intestinalepithelial cells, and catalyses the transfer of TG or CE in cells. Inthe liver and small intestine, along with the synthesis ofapolipoprotein (apolipoprotein B100 in the liver and apolipoprotein B48in the small intestine), TG and CE are combined with respectiveapolipoprotein B by the transfer activity of MTP, and thus VLDL orchylomicron is formed. As a result, those lipoproteins are secretedoutside the cells as VLDL in the liver or as chylomicron in the smallintestine. It should be said that MTP is indispensable for theconstruction of those lipoproteins. Namely, if the activity of MTP isblocked, the transfer of lipid such as TG and CE, etc. to apolipoproteinis inhibited, whereby formation of a lipoprotein can be inhibited.

On the other hand, it has been elucidated that LDL in general is closelyrelated to the progression of arteriosclerosis. That is, LDL permeatingendothelium of blood vessels is deposited in intercellular matrix ofvessel wall, where oxidative denaturation takes place and lipidperoxides or denaturated proteins induce a series of inflammationreactions. Consequently, macrophage invasion, leading to lipid depositor foaming cells, migration or proliferation of smooth muscle cells andincrease in intercellular matrix, etc. take place, which leads to thedevelopment of arteriosclerosis plaque. On the basis of the above, it issupposed to be possible to prevent or treat arteriosclerosis, coronaryartery diseases or hypertension by reducing the level of LDL.

As already mentioned, it is possible to inhibit the formation oflipoprotein such as chylomicron, VLDL, LDL, etc. by inhibiting theaction of MTP. Accordingly, it has been expected that it should becomepossible to control lipoprotein such as TG, cholesterol and LDL, etc. inblood and to control lipid in cells by adjusting the activity of MTP,and therefore, a novel agent for the treatment or prophylaxis ofhyperlipidemia, arteriosclerosis, coronary artery diseases, diabetes,obesity, or hypertension, and further, an agent for the treatment orprophylaxis of pancreatitis, hypercholesterolemia, hyperglyceridemia,etc. has been expected to be provided.

However, with the development of MTP inhibitors, some cases of fattyliver were reported and concern over hepatotoxicity has been raised.

For these reasons, a novel MTP inhibitor causing no side effect such asa fatty liver, etc. has been strongly desired.

In the conventional manners, combined therapies of various combinationsof different antihyperlipidemic drugs have been tried. However, when,for example, astatin-type drug and a resin-type drug are given together,undesirable side effects such as increased GTO and GPT, constipation,blocking of absorption of vitamin A, D, E and K and the like areobserved. On the other hand, when a statin-type drug and a fibrate drugare given together, side effects such as rhabdomyolysis or increased CPK(creative phosphokinase) are observed. Thus, with regard to a combinedtherapy for hyperlipidemia, a medicament for a combined administrationwhich can be administered in combination with a conventionalantihyperlipidemic drug without causing any above-mentioned side effecthas been desired.

Meanwhile, examples of the known compound having MTP inhibitory activitywith a similar structure of the compounds of the present invention aredescribed below.

The following compound is disclosed in WO97/26240.

The following compound is disclosed in WO97/43257.

The following compound is disclosed in WO98/23593.

The following compound is disclosed in WO99/63929.

The following compound is disclosed in WO2000/5201.

The following compound is disclosed in J. Med. Chem. (2001), 44(6) p.851-856.

The following compound is disclosed in EP 1099701.

The following compound is disclosed in WO2001/77077.

The following compound is disclosed in J. Med. Chem. (2001), 44(6) p.4677-4687.

The following compound is disclosed in WO2002/4403.

In the above literatures, however, there is no disclosure of a compoundcomprising ester as the essential structure as that disclosed in thepresent invention, much less the disclosure of the data indicating thatwhen a compound has the structure disclosed in the present invention,the compound selectively inhibits MTP in the small intestine whilerarely affects MTP in the liver.

DISCLOSURE OF THE INVENTION

Although the development of new antihyperlipidemic drugs working due toits MTP inhibitory activity has been advanced nowadays, those drugs arenot satisfactory in terms of the level of action and the accompanyingside effect such as a fatty liver, etc. Thus, the development of anantihyperlipidemic drug causing no side effect against the liver that isseen in the case of conventional MTP inhibitors and also havingexcellent MTP inhibitory activity has been strongly desired.

The inventors and those involved in the present invention have carriedout intensive studies to provide a novel MTP inhibitor causing noabove-mentioned side effect such as a fatty liver. As a result, theyhave found that an MTP inhibitor, which selectively inhibits MTP in thesmall intestine but substantially does not inhibit MTP in the liver,significantly lowers the level of unnecessary TG or cholesterol withoutcausing a side effect such as a fatty liver, etc. Surprisingly, theyhave also found that the compound having ester structure represented bythe below-mentioned formula (1) is immediately metabolized in the smallintestine, blood or liver, which makes it possible for the compound toselectively affect MTP in the small intestine without substantiallyinhibiting MTP in the liver.

To be more specific, according to the conventional drug design conceptfor the preparation of a prodrug, the carboxylic acid which is theactive principle is esterified to improve the absorption rate in thesmall intestine and is immediately metabolized in blood to reproducecarboxylic acid which is the active principle. On the other hand, a drugdesign concept that is different from the above concept for thepreparation of a prodrug is used in the present invention. Namely, byintroducing at least one ester in a molecular body of a compound havingMTP inhibitory activity, the compound is, after it exerts MTP inhibitoryactivity on mucous membranes of the small intestine, immediatelymetabolized by an esterase or a metabolic enzyme, etc. in the smallintestine, portal (blood) and liver to be transformed to correspondingcarboxylic acid and alcohol which do not have MTP inhibitory activity.This is completely a new concept, by means of which MTP in the liver isnot substantially affected and MTP in the small intestine is selectivelyinhibited. Further, the compounds of the present invention show strongMTP inhibitory activity in vitro, thus potently inhibit MTP in the smallintestine and significantly lower triglyceride and cholesterol in blood.In addition, the compounds of the present invention significantly lowernon-HDL cholesterol and, surprisingly, increase plasma HDL cholesterol.

Accordingly, the inventors of the present invention have found that whena compound comprises the ester structure represented by thebelow-mentioned formula (1), the compound is immediately metabolized inthe small intestine, blood or liver after it strongly inhibits MTP inthe small intestine and hence MTP in the liver is not substantiallyinhibited, whereby they have completed the present invention.

Thus, the present invention relates to

-   (1) An ester compound represented by the formula (1)

-    wherein

R¹ and R² are each hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆ alkyloxy, optionally substitutedC₆-C₁₄ aryl, optionally substituted C₇-C₁₆ aralkyl, optionallysubstituted C₆-C₁₄ aryloxy, optionally substituted C₇-C₁₆ aralkyloxy,optionally substituted C₇-C₁₅ arylcarbonyl, optionally substitutedheterocycle, C₂-C₇ alkoxycarbonyl, halogen, C₂-C₆ alkenyl, —N(R⁴⁰)(R⁴¹)wherein R⁴⁰ and R⁴¹ are each independently hydrogen or optionallysubstituted C₆-C₁₄ aryl;

ring A is C₆-C₁₄ aryl, heterocycle, or

-   -   X is —COO—(CH₂)_(n)—, —CON(R¹⁰)-(CH₂)_(n)— or        —N(R¹⁰)—CO—(CH₂)_(n)— wherein R¹⁰ is hydrogen, C₁-C₆ alkyl or        C₃-C₇ cycloalkyl and n is an integer of 0 to 3;

R³ and R⁴ are each independently hydrogen, hydroxy, halogen, optionallysubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, C₇-C₁₆aralkyloxy, C₁-C₆ acyl, optionally substituted heterocycle, —CON(R¹¹)(R¹²) (wherein R¹¹ and R¹² are each independently hydrogen, C₁-C₆ alkyl,optionally substituted C₆-C₁₄ aryl, optionally substituted C₇-C₁₆aralkyl, C₁-C₆ alkoxy, or R¹¹ and R¹² may be taken together with thenitrogen to which they are attached to form

wherein p is an integer of 0 to 2), —(CH₂)_(q)-N(R¹³)(R¹⁴) (wherein R¹³and R¹⁴ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₇alkoxycarbonyl, C₁-C₆ acyl, or R¹³ and R¹⁴ may be taken together withthe nitrogen to which they are attached to form

wherein p has the same meaning as defined above and q is an integer of 0to 3), or —CO(R¹⁵) (wherein R¹⁵ is hydroxy, C₁-C₆ alkoxy, optionallysubstituted C₆-C₁₄ aryloxy, optionally substituted C₇-C₁₆ aralkyloxy orC₁-C₆ alkyl);

ring B is

wherein K is an integer of 0 to 2, or ring B may be taken together withR³, R¹⁰ and the nitrogen bound to R¹⁰ to form

Alkl¹ is alkanediyl or alkenediyl;

Alkl² is alkanediyl or alkenediyl;

l is an integer of 0 to 3;

m is an integer of 0 to 3;

D is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₇ alkoxycarbonyl, —N(R⁴²)—CO(R⁴³)(wherein R⁴² is hydrogen or C₁-C₆ alkyl and R⁴³ is C₆-C₁₄ aryl or C₇-C₁₆aralkyl), or the group represented by the following formula

(wherein R⁵, R⁶ and R⁷ are each independently hydrogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₇ alkoxycarbonyl, carboxyl, halogen, cyano, nitro,halo C₁-C₆ alkyl, C₁-C₆ acyl, hydroxy, amino, optionally substitutedC₆-C₁₄ aryl, or —(CH₂)_(r)—CON(R¹⁶)(R¹⁷) (wherein R¹⁶ and R¹⁷ are eachindependently hydrogen, C₁-C₆ alkyl or halo C₁-C₆ alkyl and r is aninteger of 0 to 3);

ring C is C₆-C₁₄ aryl, C₇-C₁₅ arylcarbonylamino, C₈-C₁₇aralkylcarbonylamino, heterocycle residue, C₃-C₇ cycloalkyl or C₇-C₁₆aralkyl, or ring C may be taken together with R⁷ and R⁸ to form

R⁸ and R⁹ are each independently hydrogen, C₁-C₆ alkyl, optionallysubstituted C₆-C₁₄ aryl, hydroxy C₁-C₆ alkyl, —CON(R¹⁸) (R¹⁹) (whereinR¹⁸ and R¹⁹ are each independently hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, halo C₁-C₆ alkyl, C₂C₁₋₂ alkoxyalkyl or optionallysubstituted C₆-C₁₄ aryl), —COO(R²⁰) or —(CH₂)_(s)—OCO(R²⁰) (wherein R²⁰is hydrogen, C₁-C₆ alkyl or C₃-C₇ cycloalkyl; s is an integer of 0 to3), —N(R²¹)(R²²)(wherein R²¹ and R²² are each independently hydrogen,C₁-C₆ alkyl, C₁-C₆ acyl, C₁-C₆ alkylsulfonyl, or R²¹ and R²² may betaken together with the nitrogen to which they are attached to form

R⁸ and R⁹ may be taken together to form C₃-C₇ cycloalkyl, or a prodrugthereof, or a pharmaceutically acceptable salt of either;

-   (2) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), wherein D is    C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₇ alkoxycarbonyl or —N(R⁴²)—CO(R⁴³)    in which R⁴² and R⁴³ each has the same meaning as defined above;-   (3) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), wherein D is    the group represented by the formula

-    in which R⁵, R⁶ and R⁷ each has the same meaning as defined above;-   (4) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (3), wherein the    ring C is

-    in which q is an integer of 0 to 3;-   (5) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (2) or (4), wherein    ring B is

-   (6) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (5), wherein ring A    is

-   (7) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (6), wherein X is    —CON(R¹⁰)-(CH₂)_(n)— in which R¹⁰ and n each has the same meaning as    defined above;-   (8) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (6), wherein X is    —COO—(CH₂)_(n)— in which n has the same meaning as defined above;-   (9) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (7) or (8), wherein    n is 0;-   (10) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (10), which is    represented by the formula (1′)

-    wherein

R^(2′) and R^(2″) are each independently hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ alkoxy, halogen, halo C₁-C₆ alkyl, C₁-C₆ acyl, C₂-C₆alkenyl or cyano;

X₁ is —O— or —NR¹⁰— wherein R¹⁰ is hydrogen, C₁-C₆ alkyl or C₃-C₇cycloalkyl; and

R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, ring C, l and m each has the samemeaning as defined above,

or a prodrug thereof, or a pharmaceutically acceptable salt of either;

-   (11) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (10), wherein the    ring C is

-    in which q is an integer of 0 to 3;-   (12) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (11), wherein X₁ is    —NR¹⁰— in which R¹⁰ has the same meaning as defined above;-   (13) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (11), wherein X₁ is    —O—;-   (14) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (10) to (13),    wherein the group —(CH₂)₁— is located at the h-position of the    benzene ring in the formula (1′);-   (15) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (10) to (13),    wherein the group —(CH₂)₁— is located at the i-position of the    benzene ring in the formula (1′);-   (16) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (10) to (15),    wherein R⁸ and R⁹ are each independently —CON(R¹⁸)(R¹⁹)— in which    R¹⁸ and R¹⁹ each has the same meaning as defined above;-   (17) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (10) to (15),    wherein R⁸ and R⁹ are each independently —COO(R²⁰)— in which R²⁰ has    the same meaning as defined above;-   (18) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (12) to (17),    wherein the ring C is C₆-C₁₄ aryl;-   (19) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (18), wherein    C₆-C₁₄ aryl is phenyl;-   (20) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (12) to (17),    wherein the ring C is C₃-C₇ cycloalkyl;-   (21) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (12) to (17),    wherein the ring C is

-   (22) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-{2-[4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-ylmethyl ester,-   2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionic    acid 9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-ylmethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-(2,2,2-trifluoro-ethylcarbamoyl)-cyclopentylmethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisopropyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-(2,2,2-trifluoro-ethylcarbamoyl)-cyclohexylmethyl ester,-   2-phenyl-2-{2-[4-(2-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-{2-[4-(2-phenoxy-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-{2-[4-(2-butoxy-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-{2-[4-(2-trifluoromethyl-benzoyloxy)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-{2-[4-(2-benzoyl-benzoyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-{2-[4-(2-benzoyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dicyclohexyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-cyclohexylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-phenylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isopropylcarbamoyl-2-phenyl-ethyl ester,-   2-benzyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   2-butoxy-benzoic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   2-cyclohexyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   [4-(2-phenoxy-benzoylamino)-phenyl]-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-{2-(2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-methylcarbamoyl-2-phenyl-ethyl ester,-   2-pyridin-2-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-pyridin-3-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-phenyl    ester,-   2-phenyl-2-(2-{3-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   [4-(2-butoxy-benzoylamino)-phenyl]-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-butylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{4-[(9-oxo-9h-fluorene-1-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(9h-fluorene-1-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   [4-(2-phenoxy-benzoylamino)-phenyl]-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   [4-(2-butoxy-benzoylamino)-phenyl]-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{4-[(3′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[2-(4-fluoro-benzoyl)-benzoylamino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-2-chloro-phenyl    ester,-   2-phenyl-2-{2-[4-(2-thiophen-3-yl-benzoylamino)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-(2-{4-[(biphenyl-3-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[isopropyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[cyclohexyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[4-(2-isopropyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-{2-[4-(2-benzyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dipropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisobutyl ester,-   2-phenyl-2-{2-[4-(2-trifluoromethoxy-benzoylamino)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-{2-[4-(2-butoxycarbonyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isobutylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl ester,-   2-(2-{4-[ethyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   [4-(2-cyclohexyl-benzoylamino)-phenyl]-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-(4′-chloro-biphenyl-2-carbonyl)-amino)-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(3′,4′-dichloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2.2-bis-(2-methoxy-ethylcarbamoyl)-2-phenyl-ethyl ester,-   2-[2-(4-{[2-methyl-4-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-phenyl)-acetoxymethyl]-2-phenyl-malonic    acid diethyl ester,-   (4-{[2-methyl-4-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-phenyl)-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   (4-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-phenyl)-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   (3-methyl-4-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-phenyl)-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-benzylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(isopropyl-methyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-(ethyl-methyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(ethyl-methyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(ethyl-methyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-(piperidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-(piperidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2-propionylamino-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2-propionylamino-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-(2,5-dioxo-pyrrolidin-1-yl)-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoyl-benzyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoylmethyl-benzyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-isopropylamino-2-phenyl-ethyl ester hydrochloride,-   [3-dimethylcarbamoyl-4-(2-trifluoromethyl-benzoylamino)-phenyl]-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(2-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-fluoro-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-bromo-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-acetylamino-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid-2-butyrylamino-2-phenyl-ethyl ester,-   [4-(2-benzoyl-benzoylamino)-3-dimethylcarbamoyl-phenyl]-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-{2-[4-(2-benzoyl-benzoylamino)-3-dimethylcarbamoyl-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy    methyl)-malonic acid diethyl ester,-   2-cyclohexyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy    methyl)-malonic acid diethyl ester,-   2-(2-{4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-acetyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   [3-dimethylcarbamoyl-4-(2-phenoxy-benzoylamino)-phenyl]-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(2-phenoxy-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-cyano-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-methanesulfonylamino-2-phenyl-ethyl ester,-   3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-2-phenyl-propionic    acid ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-(methyl-propionyl-amino)-2-phenyl-ethyl ester,-   2-[3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-propyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester)-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid di-2,2,2-trifluoroethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-nitro-pyridin-2-yl)-malonic    acid diethyl ester,-   2-(5-amino-pyridin-2-yl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-pyridin-2-yl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-o-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-m-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-p-tolyl-malonic    acid diethyl ester,-   2-(2-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(4-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-succinic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(2-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(4-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-ethoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[4-(2,4-bis-trifluoromethyl-benzoylamino)-3-dimethylcarbamoyl-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-ethyl-4-trifluoromethyl-benzoylamino)-phenyl-acetoxymethyl    -2-phenyl-malonic acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-ethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropenyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(2-isopropenyl-4-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(2-isopropyl-4-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[2-(3-trifluoromethyl-phenylamino)-benzoylamino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[2-(3-trifluoromethyl-phenoxy)-benzoylamino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethyl-2-phenyl-butyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[2-(4-trifluoromethyl-phenoxy)-benzoylamino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-phenyl-cyclopropylmethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-diphenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-phenyl-cyclopentylmethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-hydroxy-2-hydroxymethyl-2-phenyl-propyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-acetoxy-2-acetoxymethyl-2-phenyl-propyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-2-yl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-3-yl-malonic    acid diethyl ester,-   2-(2-{4-dimethylcarbamoyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-pyridin-2-yl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiazol-2-yl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-isopropyl-malonic    acid diethyl ester,-   2-sec-butyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-isobutyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-propyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-ethyl-malonic    acid diethyl ester,-   2-butyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-allyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-2,2-bis-ethoxycarbonyl-propionic    acid ethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(1-methyl-butyl)-malonic    acid diethyl ester,-   2-(2-{3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino)-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-(2-{3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-propoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-methoxy-4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-morpholin-4-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-[2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-malonic    acid diethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   2-[2-(2-{4-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-isopropylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-[2-(2-{2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   {2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-[2-(2-{2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-isopropoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methoxycarbonyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-ethoxy-5-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-(9h-fluoren-9-yl)-ethyl ester,-   n-biphenyl-2-yl-terephthalamic acid    2-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[(biphenyl-2-carbonyl)-amino]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-(2-biphenyl-2-yl-acetylamino)-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-naphthalen-1-yl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-[2-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-diphenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-biphenyl-2-yl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-phenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[8-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-(2,6-dichloro-phenyl)-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl    ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-(2-chloro-phenyl)-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{2-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-{2-[4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-benzoyloxy]-ethyl}-malonic    acid diethyl ester,-   2-{2-[4-(2-benzoyl-benzoyloxy)-benzoyloxy]-ethyl}-2-phenyl-malonic    acid diethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2-chloro-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-phenyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2,6-dichloro-phenyl    ester,-   4-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-cyclohexanecarboxylic    acid 2-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-yl]-ethyl    ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-cyclohexanecarboxylic    acid 2-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-yl]-ethyl    ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-cyclohexanecarboxylic    acid 3-phenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   2-phenyl-2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-cyclohexanecarbonyloxymethyl}-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-cyclohexanecarbonyloxy}-ethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-{2-(4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-indol-1-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoimidazol-1-yl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   [2-oxo-3-(4′-trifluoromethyl-biphenyl-2-carbonyl)-2,3-dihydro-benzooxazol-6-yl]-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-{2-(3-ethoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonic    acid diethyl ester,-   4-{[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-methyl}-benzoic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   3-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionic    acid ethylcarbamoyl-phenyl-methyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid benzyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid ethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoimidazol-1-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   3-([(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-methyl)-benzoic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid methyl ester,-   2-(2-{3-benzyloxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-carboxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[2-oxo-3-(4′-trifluoromethyl-biphenyl-2-carbonyl)-2,3-dihydro-benzooxazol-6-yl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-{2-[8-oxo-7-(4′-trifluoromethyl-biphenyl-2-carbonyl)-7-aza-bicyclo[4.2.0]octa-[(6),2,4-trien-3-yl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(3-dimethylcarbamoyl-4-{[1-(2-nitrol-4-trifluoro-methyl-phenyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetoxymethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-acetylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(4-methyl-thiazol-2-yl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-biphenyl-3-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-formyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylaminomethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(methoxy-methyl-carbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyryl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester, and-   2-(2-{3-(1-hydroxy-2-methyl-propyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester;-   (23) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-{2-[4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-ylmethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionic    acid 9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-ylmethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{4-[4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisopropyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dicyclohexyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-cyclohexylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-phenylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isopropylcarbamoyl-2-phenyl-ethyl ester,-   2-benzyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl-malonic    acid diethyl ester,-   2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl-2-phenyl-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   2-cyclohexyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-methylcarbamoyl-2-phenyl-ethyl ester,-   2-pyridin-2-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl-malonic    acid diethyl ester,-   2-pyridin-3-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-phenyl    ester,-   2-phenyl-2-(2-{3-trifluoromethyl-4-[(4′-trifluoro-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-butylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{4-[(4′-methyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methoxy-biphenyl-2-carbonyl}-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{4-[(3′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-2-chloro-phenyl    ester,-   2-(2-{4-[isopropyl-(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[cyclohexyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dipropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisobutyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 2,2-bis-isobutylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 2,2-bis-(3-methyl-butylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{4-[ethyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-(ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(3′,4′-dichloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-(ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 2,2-bis-(2-methoxy-ethylcarbamoyl)-2-phenyl-ethyl ester,-   2-(2-{3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-ethyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-benzylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4′-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(isopropyl-methylcarbamoyl)-4-[(4′-trifluoro-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoro-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-(piperidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-ethyl ester,-   {3-(dimethylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethyl-carbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-(piperidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2-propionylamino-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl∇-acetic    acid 2-phenyl-2-propionylamino-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-(2,5-dioxo-pyrrolidin-1-yl)-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoyl-benzyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl}-amino]-phenyl}-acetic    acid 2-ethylcarbamoylmethyl-benzyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-isopropylamino-2-phenyl-ethyl ester hydrochloride,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-fluoro-biphenyl-2-carbonyl}-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-bromo-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-acetylamino-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-butyrylamino-2-phenyl-ethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-cyclohexyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-acetyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-cyano-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-methanesulfonylamino-2-phenyl-ethyl ester,-   3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-2-phenyl-propionic    acid ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-(methyl-propionyl-amino)-2-phenyl-ethyl ester,-   2-[3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-propyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid di-2,2,2-trifluoroethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-nitro-pyridin-2-yl)-malonic    acid diethyl ester,-   2-(5-amino-pyridin-2-yl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-pyridin-2-yl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-o-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-m-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-p-tolyl-malonic    acid diethyl ester,-   2-(2-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(4-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-succinic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(2-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(4-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{4-(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl}-malonic    acid diethyl ester,-   2-(2-{4-(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-ethoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{4-[(5,4′-bis-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-(2,4-bis-trifluoromethyl-benzoylamino)-3-dimethylcarbamoyl-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(2-ethyl-4-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-ethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropenyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethyl-2-phenyl-butyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-phenyl-cyclopropylmethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-diphenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-phenyl-cyclopentylmethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-hydroxy-2-hydroxymethyl-2-phenyl-propyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-acetoxy-2-acetoxymethyl-2-phenyl-propyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-2-yl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-3-yl-malonic    acid diethyl ester,-   2-(2-{4-dimethylcarbamoyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-pyridin-2-yl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiazol-2-yl-malonic    acid diethyl ester,-   2-(2-{3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-(2-{3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-propoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {2-{3-morpholin-4-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-[2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-malonic    acid diethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   2-[2-(2-{4-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-isopropylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino)-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-[2-(2-{2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   {2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-[2-(2-{2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-isopropoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methoxycarbonyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-ethoxy-5-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[9h-fluoren-9-yl]-ethyl ester,-   n-biphenyl-2-yl-terephthalamic acid    2-[9-(2,2,2-trifluoro-ethylcarbamoyl)-9h-fluoren-9-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[(biphenyl-2-carbonyl)-amino]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-(2-biphenyl-2-yl-acetylamino)-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-naphthalen-1-yl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-[2-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-diphenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-biphenyl-2-yl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-phenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[8-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-[(2,6-dichloro-phenyl)-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl    ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-(2-chloro-phenyl)-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   2-phenyl-2-(2-(4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{2-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-{2-[4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-benzoyloxy]-ethyl}-malonic    acid diethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbony)-2-chloro-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-phenyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2,6-dichloro-phenyl    ester,-   2-(2-{3-ethoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionic    acid ethylcarbamoyl-phenyl-methyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid benzyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid ethyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid methyl ester,-   2-(2-{3-benzyloxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-carboxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-acetylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(4-methyl-thiazol-2-yl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-biphenyl-3-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-formyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylaminomethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-3-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxy-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-3-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyryl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-3-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester, and-   2-(2-{3-(1-hydroxy-2-methyl-propyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester;-   (24) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl)-2-phenyl-ethyl ester,-   2-phenyl-2-{2-[4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[methyl-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-2-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-phenyl-ethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisopropyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dicyclohexyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-cyclohexylcarbamoyl-2-phenyl ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-phenylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isopropylcarbamoyl-2-phenyl-ethyl ester,-   2-benzyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   2-cyclohexyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-methylcarbamoyl-2-phenyl-ethyl ester,-   2-pyridin-2-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-pyridin-3-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carbxylic acid    4-(2,2-bis-ethylcarbamoyl)-2-phenyl-ethoxycarbonylmethyl)-phenyl    ester,-   2-phenyl-2-(2-{3-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-butylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{4-[(3′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl)-2-phenyl-ethoxycarbonylmethyl)-2-chloro-phenyl    ester,-   2-(2-{4-[isopropyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[cyclohexyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dipropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisobutyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isobutylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl ester,-   2-(2-{4-[ethyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(3′4′-dichloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(2-methoxy-ethylcarbamoyl)-2-phenyl-ethyl ester,-   2-(2-{3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-benzylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino)-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(isopropyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-(piperidin-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidin-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-pyrrolidin-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-piperidin-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2-propionylamino-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-(2,5-dioxo-pyrrolidin-1-yl)-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoyl-benzyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethylcarbamoylmethyl-benzyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-isopropylamino-2-phenyl-ethyl ester hydrochloride,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-fluoro-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-bromo-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-acethylamino-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-butyrylamino-2-phenyl-ethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-cyclohexyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-acetyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-cyano-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4-methyl-4′-trifluromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-methanesulfonylamino-2-phenyl-ethyl ester,-   3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-2-phenyl-propionic    acid ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-(methyl-propionyl-amino)-2-phenyl-ethyl ester,-   2-[3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-propyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methoxy-4′-trifluromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid di-2,2,2-trifluoroethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-((2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-nitro-pyridin-2-yl)-malonic    acid diethyl ester,-   2-(5-amino-pyridin-2-yl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-pyridin-2-yl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2o-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-m-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-p-tolyl-malonic    acid diethyl ester,-   2-(2-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(4-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-succinic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(2-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(4-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-ethoxy-4′-trifluromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{4-(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-(2,4-bis-trifluoromethyl-benzoylamino)-3-dimethylcarbamoyl-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-[(2-ethyl-4-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-ethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropenyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-ethyl-2-phenyl-butyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-phenyl-cyclopropylmethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-diphenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 1-phenyl-cyclopentylmethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-hydroxy-2-hydroxymethyl-2-phenyl-propyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-acetoxymethyl-2-phenyl-propyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl]-2-thiophen-2-yl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl]-2-thiophen-3-yl-malonic    acid diethyl ester,-   2-(2-{4-dimethylcarbamoyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-pyridin-2-yl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl]-2-(3-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiazol-2-yl-malonic    acid diethyl ester,-   2-(2-{3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-(2-{3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-propoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-(2-{3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxy-4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   {3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-morpholin-4-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-[2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-malonic    acid diethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   2-[2-{2-[4-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-isopropylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-[2-{2-(2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   {2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   2-[2-(2-{2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-isopropoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methoxycarbonyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-ethoxy-5-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[(biphenyl-2-carbonyl)-amino]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-(2-biphenyl-2-yl-acetylamino)-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-naphthalen-1-yl-3-(2,2,2-trifluoroethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-[2-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-diphenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-biphenyl-2-yl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-phenyl-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    2-[8-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-(2,6-dichloro-phenyl)-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl    ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-(2-chloro-phenyl)-3-(2,2,2-trifluoro-ethylcarbamoyl)-propyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{2-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-{2-[4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-benzoyloxy]-ethyl}-malonic    acid diethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2-chloro-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-phenyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2,6-dichloro-p    henyl ester,-   2-(2-{3-ethoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonic    acid diethyl ester,-   3-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionic    acid ethylcarbamoyl-phenyl-methyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid benzyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid ethyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid methyl ester,-   2-(2-{3-benzyloxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-carboxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-acetylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(4-methyl-thiazol-2-yl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-biphenyl-3-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-formyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylaminomethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(methoxy-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyryl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester, and-   2-(2-{3-(1-hydroxy-2-methyl-propyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester;-   (25) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-cyclohexylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-phenylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isopropylcaramoyl-2-phenyl-ethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-methylcarbamoyl-2-phenyl-ethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-phenyl    ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-butylcarbamoyl-2-phenyl-ethyl-ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl ethyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-2-chloro-phenyl    ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isobutylcarbamoyl-2-phenyl ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(3-methyl-butylcarbamoyl)-2-phenyl ethyl ester,-   {4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl ethyl ester,-   {4-[(3′,4′-dichloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl)-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl)-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(2-methoxy-ethylcarbamoyl)-2-phenyl-ethyl ester,-   {3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-phenyl-ethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-benzylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(isopropyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-(piperidin-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidin-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-propoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-isopropylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propylcarbamoyl-propyl ester,-   {2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2-chloro-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-phenyl ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2,6-dichloro-phenyl    ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid benzyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid ethyl ester, and-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid methyl ester;-   (26) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   2-phenyl-2-{2-[4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisopropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dicyclohexyl ester,-   2-benzyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-cyclohexyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-pyridin-2-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-pyridin-3-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(3′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[isopropyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[cyclohexyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dipropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisobutyl ester,-   2-(2-{4-[ethyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-bromo-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-cyclopentyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-cyclohexyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-acetyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-cyano-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-propyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-nitro-pyridin-2-yl)-malonic    acid diethyl ester,-   2-(5-amino-pyridin-2-yl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-pyridin-2-yl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-o-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-m-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-p-tolyl-malonic    acid diethyl ester,-   2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(4-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-succinic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(2-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(4-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl)-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-ethoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl)-malonic    acid diethyl ester,-   2-[2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-ethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropenyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-2-yl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-3-yl-malonic    acid diethyl ester,-   2-(2-{4-dimethylcarbamoyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-pyridin-2-yl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiazol-2-yl-malonic    acid diethyl ester,-   2-(2-{3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-{2-(3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-morpholin-4-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-[2-(2-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-malonic    acid diethyl ester,-   2-[2-(2-{4-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-ethoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-isopropoxy-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-methoxycarbonyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{2-ethoxy-5-methyl-3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl]-malonic    acid diethyl ester,-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{2-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-{2-[4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-benzoyloxy]-ethyl}-malonic    acid diethyl ester,-   2-(2-{3-ethoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-benzyloxycarbony-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-carboxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-acetylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(4-methyl-thiazol-2-yl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-biphenyl-3-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-formyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylaminomethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(methoxy-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyryl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester, and-   2-(2-{3-(1-hydroxy-2-methyl-propyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester;-   (27) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-cyclohexylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-phenylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isopropylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethyl ester,-   2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-methylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-butylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethyl-carbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl-ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3-phenyl-3,3-bis-propyl-carbamoyl-propyl ester,-   {4-[(biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-isobutylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl ester,-   {4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {4-[(3′,4′-dichloro-biphenyl-2-carbonyl)-amino]-phenyl}-acetic acid    2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-(2-methoxy-ethylcarbamoyl)-2-phenyl-ethyl ester,-   {3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethyl-carbamoyl-3-phenyl-propyl ester,-   {3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethyl-carbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-benzylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 4,4-bis-ethylcarbamoyl-4-phenyl-butyl ester,-   {3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(isopropyl-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(ethyl-methylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-(piperidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(methyl-propylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2-phenyl-2,2-bis-propylcarbamoyl-ethyl ester,-   {3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   {3-propoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3,3-bis-ethylcarbamoyl-3-phenyl-propyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid benzyl ester,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid,-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid ethyl ester, and-   5-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonyl-methyl)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic    acid methyl ester;-   (28) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisopropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dicyclohexyl ester,-   2-benzyl-2-(2-[{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-cyclohexyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-pyridin-2-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-pyridin-3-yl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(3′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[isopropyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[cyclohexyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid dipropyl ester,-   2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diisobutyl ester,-   2-(2-{4-[ethyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-ethyl-4-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropyl-4-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyl-4-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-4-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   {3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   {3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetic    acid 2,2-bis-ethylcarbamoyl-2-phenyl-ethyl ester,-   2-phenyl-2-(2-{3-(pyrrolidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-(piperidine-1-carbonyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-fluoro-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-bromo-biphenyl-2-carbonyl)-amino]}-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid dimethyl ester,-   2-cyclopentyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-cyclohexyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-acetyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(4′-cyano-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-propyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid 2,2,2-trifluoroethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-4-[(2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-nitro-pyridin-2-yl)-malonic    acid diethyl ester,-   2-(5-amino-pyridin-2-yl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-pyridin-2-yl-malonic    acid diethyl ester,-   2-(2-{3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-o-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-m-tolyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-p-tolyl-malonic    acid diethyl ester,-   2-(2-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(4-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-succinic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(2-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(4-methoxy-phenyl)-malonic    acid diethyl ester,-   2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(6-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-ethoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-[2-(2-{4-(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxy)-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-(6-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-(3-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-{4-(2,4-bis-trifluoromethyl-benzoylamino)-3-dimethylcarbamoyl-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(2-ethyl-4-trifluoromethyl-benzoylamino)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-ethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropenyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-2-yl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiophen-3-yl-malonic    acid diethyl ester,-   2-(2-{4-dimethylcarbamoyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-pyridin-2-yl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(5-methyl-thiophen-2-yl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-thiazol-2-yl-malonic    acid diethyl ester,-   2-(2-{3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-piperidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-phenyl-2-(2-{3-pyrrolidin-1-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-morpholin-4-yl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-diethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{2-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-ethoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-benzyloxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-carboxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isopropoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-acetylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-methoxycarbonylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(4-methyl-thiazol-2-yl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-phenyl-2-(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-biphenyl-3-yl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-formyl-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylaminomethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-(methoxy-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester,-   2-(2-{3-isobutyryl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester, and-   2-(2-{3-(1-hydroxy-2-methyl-propyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonic    acid diethyl ester;-   (29) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   biphenyl-2-carboxylic acid    4-[2-phenyl-2,2-bis-(2,2,2-trifluoro-ethylcarbamoyl)-ethoxycarbonylmethyl]-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(2,2-bis-ethylcarbamoyl-2-phenyl-ethoxycarbonylmethyl)-2-chloro-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonylmethyl)-2-chloro-phenyl    ester,-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-phenyl ester,    and-   4′-trifluoromethyl-biphenyl-2-carboxylic acid    4-(3,3-bis-ethylcarbamoyl-3-phenyl-propoxycarbonyl)-2,6-dichloro-p    henyl ester;-   (30) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   2-phenyl-2-{2-[4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-malonic    acid diethyl ester,-   2-{2-[3-dimethylcarbamoyl-4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl-malonic    acid diethyl ester,-   2-{2-[3-methoxy-4-(4′-trifluoromethyl-biphenyl-2-carbonyloxy)-phenyl]-acetoxymethyl}-2-phenyl    malonic acid diethyl ester, and-   4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoic acid    3-[2-(2,2,2-trifluoro-ethylcarbamoyl)-naphthalen-1-yl]-propyl ester;-   (31) The ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to the above (1), which is    selected from the group consisting of-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-isopropyl-malonic    acid diethyl ester,-   2-sec-butyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-isobutyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-propyl-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-ethyl-malonic    acid diethyl ester,-   2-butyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-allyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic    acid diethyl ester,-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-2,2-bis-ethoxycarbonyl-propionic    acid ethyl ester, and-   2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(1-methyl-butyl)-malonic    acid diethyl ester;-   (32) A pharmaceutical composition, which comprises the ester    compound or a prodrug thereof, or a pharmaceutically acceptable salt    of either according to any of the above (1) to (31) and a    pharmaceutically acceptable carrier;-   (33) An MTP (microsomal triglyceride transfer protein) inhibitor,    which comprises the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either according to any of the    above (1) to (31) as an active ingredient;-   (34) An agent for the treatment or prophylaxis of hyperlipidemia,    which comprises the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either according to any of the    above (1) to (31) as an active ingredient;-   (35) An agent for the treatment or prophylaxis of arteriosclerosis,    which comprises the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either according to any of the    above (1) to (31) as an active ingredient;-   (36) An agent for the treatment or prophylaxis of coronary artery    diseases, which comprises the ester compound or a prodrug thereof,    or a pharmaceutically acceptable salt of either according to any of    the above (1) to (31) as an active ingredient;-   (37) An agent for the treatment or prophylaxis of obesity, which    comprises the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either according to any of the    above (1) to (31) as an active ingredient;-   (38) An agent for the treatment or prophylaxis of diabetes, which    comprises the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either according to any of the    above (1) to (31) as an active ingredient;-   (39) An agent for the treatment or prophylaxis of hypertension,    which comprises the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either according to any of the    above (1) to (31) as an active ingredient;-   (40) An agent for the treatment or prophylaxis of hyperlipidemia,    arteriosclerosis, coronary artery diseases, obesity, diabetes or    hypertension, which comprises MTP inhibitor selectively inhibiting    MTP (microsomal triglyceride transfer protein) in the small    intestine and a pharmaceutically acceptable carrier;-   (41) The agent for the treatment or prophylaxis according to the    above (40), wherein the MTP inhibitor does not substantially inhibit    MTP in the liver but substantially inhibits only MTP in the small    intestine;-   (42) The agent for the treatment or prophylaxis according to the    above (41), wherein after the administered MTP inhibitor inhibits    MTP in the small intestine, it is metabolized in the small    intestine, blood and liver to the amount at which the remaining MTP    inhibitor in the liver does not substantially inhibit the MTP in the    liver;-   (43) The agent for the treatment or prophylaxis according to the    above (42), wherein the remaining MTP inhibitor in the liver is    metabolized to the state where TG-releasing activity of the liver is    kept at the level of about 80% or more of the normal level;-   (44) The agent for the treatment or prophylaxis according to the    above (40) to (43), wherein the MTP inhibitor is a compound having    at least one ester bond;-   (45) The agent for the treatment or prophylaxis according to the    above (44), wherein after the compound having at least one ester    bond exerts MTP inhibitory activity, the ester moiety of the    compound is metabolized in blood to become an inactive substance;-   (46) The agent for the treatment or prophylaxis according to the    above (40) to (45), wherein the MTP inhibitor is the ester compound    or a prodrug thereof, or a pharmaceutically acceptable salt of    either mentioned in any of the above (1) to (31);-   (47) A method for the treatment or prophylaxis of hyperlipidemia,    arteriosclerosis, coronary artery diseases, obesity, diabetes or    hypertension, which comprises administering a compound selectively    inhibiting MTP (microsomal triglyceride transfer protein) in the    small intestine;-   (48) The method according to the above (47), wherein after the    compound inhibits MTP in the small intestine, it is metabolized in    the small intestine, blood and liver to the amount at which    remaining said compound in the liver does not substantially inhibit    MTP in the liver;-   (49) The method according to the above (47), wherein the remaining    compound in the liver is metabolized to the state where TG-releasing    activity of the liver is kept at the level of about 80% or more of    the normal level;-   (50) The method according to the above (47) to (49), wherein the    compound has at least one ester bond;-   (51) The method according to the above (50), wherein after the    compound having at least ester bond exerts MTP inhibitory activity,    the ester moiety of the compound is metabolized in blood to become    an inactive substance;-   (52) The method according to the above (47) to (52), wherein the    compound is the ester compound or a prodrug thereof, or a    pharmaceutically acceptable salt of either mentioned in any of the    above (1) to (31);-   (53) The agent for the treatment or prophylaxis according to the    above (40) to (46), wherein the agent is an agent for the treatment    or prophylaxis of hyperlipidemia which is used in combination with    other antihyperlipidemic drug(s);-   (54) The agent for the treatment or prophylaxis according to the    above (53), wherein other antihyperlipidemic drug is a statin-type    drug;-   (55) The agent for the treatment or prophylaxis according to the    above (54), wherein the statin-type drug is one or more drug(s)    selected from the group consisting of lovastatin, simvastatin,    pravastatin, fluvastatin, atorvastatin and cerivastatin;-   (56) The agent for the treatment or prophylaxis according to the    above (40) to (46), wherein the agent is an agent for the treatment    or prophylaxis of obesity which is used in combination with other    anti-obesity drug(s);-   (57) The agent for the treatment or prophylaxis according to the    above (56), wherein other anti-obesity drug is mazindol or/and    orlistat;-   (58) The agent for the treatment or prophylaxis according to the    above (40) to (46), wherein the agent is an agent for the treatment    or prophylaxis of diabetes which is used in combination with other    anti-diabetic drug(s);-   (59) The agent for the treatment or prophylaxis according to the    above (58), wherein other anti-diabetic drug is one or more drug(s)    selected from the group consisting of insulin preparations,    sulfonylurea drugs, insulin secretagogues, sulfonamide drugs,    biguanide drugs, α-glucosidase inhibitors and insulin    resistance-improving drugs;-   (60) The agent for the treatment or prophylaxis according to the    above (59), wherein other anti-diabetic drug is one or more drug(s)    selected from the group consisting of insulin, glibenclamide,    tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide,    gliclazide, nateglinide, glybuzole, metformin hydrochloride,    buformin hydrochloride, boglibose, acarbose and pioglitazone    hydrochloride;-   (61) The agent for the treatment or prophylaxis according to the    above (40) to (46), wherein the agent is an agent for the treatment    or prophylaxis of hypertension which is used in combination with    other anti-hypertension drug(s);-   (62) The agent for the treatment or prophylaxis according to the    above (61), wherein other anti-hypertension drug is one or more    drug(s) selected from the group consisting of loop diuretics,    angiotensin converting enzyme inhibitors, angiotensin II receptor    antagonists, calcium antagonists, β-blockers, α,β-blockers and    α-blockers;-   (63) The agent for the treatment or prophylaxis according to the    above (62), wherein other anti-hypertension drug is one or more    drug(s) selected from the group consisting of furosemide delayed    release, captopril, captopril delayed release, enalapril maleate,    alacepril, delapril hydrochloride, silazapril, lisinopril,    benazepril hydrochloride, imidapril hydrochloride, temocapril    hydrochloride, quinapril hydrochloride, trandolapril, perindopril    erbumine, losartan potassium, candesartan cilexetil, nicardipine    hydrochloride, nicardipine hydrochloride delayed release,    nilvadipine, nifedipine, nifedipine delayed release, benidipine    hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride    delayed release, nisoldipine, nitrendipine, manidipine    hydrochloride, barnidipine hydrochloride, efonidipine hydrochloride,    amlodipine besylate, felodipine, cilnidipine, aranidipine,    propranolol hydrochloride, propranolol hydrochloride delayed    release, pindolol, pindolol delayed release, indenolol    hydrochloride, carteolol hydrochloride, carteolol hydrochloride    delayed release, bunitrolol hydrochloride, bunitrolol hydrochloride    delayed release, atenolol, asebutolol hydrochloride, metoprolol    tartrate, metoprolol tartrate delayed release, nipradilol,    penbutolol sulfate, tilisolol hydrochloride, carvedilol, bisoprolol    fumarate, betaxolol hydrochloride, celiprolol hydrochloride,    bopindolol malonate, bevantolol hydrochloride, labetalol    hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride,    prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate,    bunazocin hydrochloride, bunazocin hydrochloride delayed release,    urapidil and phentolamine mesylate;-   (64) Use of the agent for the treatment or prophylaxis according to    the above (34) to (46) and other antihyperlipidemic drug(s) for the    treatment or prophylaxis of hyperlipidemia;-   (65) The use according to the above (64), wherein other    antihyperlipidemic drug is a statin-type drug;-   (66) The use according to the above (64), wherein the statin-type    drug is one or more drug(s) selected from the group consisting of    lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and    cerivastatin;-   (67) Use of the agent for the treatment or prophylaxis according to    the above (34) to (46) and other anti-obesity drug(s) for the    treatment or prophylaxis of obesity;-   (68) The use according to the above (67), wherein other anti-obesity    drug is mazindol or/and orlistat;-   (69) Use of the agent for the treatment or prophylaxis according to    the above (34) to (46) and other anti-diabetic drug(s) for the    treatment or prophylaxis of diabetes;-   (70) The use according to the above (69), wherein other    anti-diabetic drugs are one or more drug(s) selected from the group    consisting of insulin preparations, sulfonylurea drugs, insulin    secretagogues, sulfonamide drugs, biguanide drugs, α-glucosidase    inhibitors and insulin resistance improving drugs;-   (71) The use according to the above (70), wherein other    anti-diabetic drug is one or more drug(s) selected from the group    consisting of insulin, glibenclamide, tolbutamide, glyclopyramide,    acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide,    glybuzole, metformin hydrochloride, buformin hydrochloride,    boglibose, acarbose and pioglitazone hydrochloride;-   (72) Use of the agent for the treatment or prophylaxis according to    the above (34) to (46) and other anti-hypertension drug(s) for the    treatment or prophylaxis of hypertension;-   (73) The use according to the above (72), wherein other    anti-hypertension drug is one or more drug(s) selected from the    group consisting of loop diuretics, angiotension converting enzyme    inhibitors, angiotension II receptor antagonists, calcium    antagonists, beta-blockers, alpha/beta blockers and alpha blockers;-   (74) The use according to the above (73), wherein other    anti-hypertension drug is one or more drug(s) selected from the    group consisting of furosemide delayed release, captopril, captopril    delayed release, enalapril maleate, alacepril, delapril    hydrochloride, silazapril, lisinopril, benazepril hydrochloride,    imidapril hydrochloride, temocapril hydrochloride, quinapril    hydrochloride, trandolapril, perindopril erbumine, losartan    potassium, candesartan cilexetil, nicardipine hydrochloride,    nicardipine hydrochloride delayed release, nilvadipine, nifedipine,    nifedipine delayed release, benidipine hydrochloride, diltiazem    hydrochloride, diltiazem hydrochloride delayed release, nisoldipine,    nitrendipine, manidipine hydrochloride, barnidipine hydrochloride,    efonidipine hydrochloride, amlodipine besylate, felodipine,    cilnidipine, aranidipine, propranolol hydrochloride, propranolol    hydrochloride delayed release, pindolol, pindolol delayed release,    indenolol hydrochloride, carteolol hydrochloride, carteolol    hydrochloride delayed release, bunitrolol hydrochloride, bunitrolol    hydrochloride delayed release, atenolol, asebutolol hydrochloride,    metoprolol tartrate, metoprolol tartrate delayed release,    nipradilol, penbutolol sulfate, tilisolol hydrochloride, carvedilol,    bisoprolol fumarate, betaxolol hydrochloride, celiprolol    hydrochloride, bopindolol malonate, bevantolol hydrochloride,    labetalol hydrochloride, arotinolol hydrochloride, amosulalol    hydrochloride, prazosin hydrochloride, terazosin hydrochloride,    doxazosin mesylate, bunazocin hydrochloride, bunazocin hydrochloride    delayed release, urapidil and phentolamine mesylate;-   (75) A pharmaceutical composition comprising an effective amount of    the ester compound or a prodrug thereof, or a pharmaceutically    acceptable salt of either according to any of the above (1) to (31),    a pharmaceutically acceptable, appropriate amount of ethanol and    propylene glycol fatty acid ester;-   (76) The pharmaceutical composition according to the above (75),    which comprises 25 to 35% by weight of ethanol and 65 to 75% by    weight of propylene glycol fatty acid ester;-   (77) A capsule formulation comprising the pharmaceutical composition    according to the above (75) or (76);-   (78) The capsule formulation according to the above (77), wherein    the capsule formulation is a hard capsule or soft capsule;-   (79) A biphenyl compound represented by the formula (100)

-    wherein

R^(1′) is hydrogen, C₁-C₆ alkyl, halogen, halo C₁-C₆ alkyl or C₁-C₆alkoxy;

R^(2′″) is hydrogen, C₁-C₆ alkyl, halogen, halo C₁-C₆ alkyl or C₂-C₆alkenyl;

R^(3″) is CON(R^(11a)) (R^(12a)) wherein R^(11a) and R^(12a) are eachindependently hydrogen, C₁-C₆ alkyl, optionally substituted C₆-C₁₄ aryl,optionally substituted C₇-C₁₆ aralkyl, C₁-C₆ alkoxy, or R^(11a) andR^(12a) may be taken together with the nitrogen to which they areattached to form

(in which p is an integer of 0 to 2);

R^(4′) is hydrogen, halogen, C₁-C₆ alkyl or halo C₁-C₆ alkyl;

R⁵⁰ is hydrogen, C₁-C₆ alkyl, optionally substituted C₆-C₁₄ aryl oroptionally substituted C₇-C₁₆ aralkyl; and

1 a is an integer of 1 to 3,

or a prodrug thereof, or a pharmaceutically acceptable salt of either;and

-   (80) The biphenyl compound according to the above (79),-    wherein

R^(1′) is hydrogen,

R^(2′″) is halo C₁-C₆ alkyl,

R^(3″) is —CON(R^(11b))(R^(12b)) wherein R^(11b) and R^(12b) are eachindependently hydrogen or C₁-C₆ alkyl, or R^(11b) and R^(12b) may betaken together with the nitrogen to which they are attached to form.

(in which p is an integer of 0 to 2),

R^(4′) is hydrogen, and

R⁵⁰ is hydrogen or C₁-C₆ alkyl,

or a prodrug thereof, or a pharmaceutically acceptable salt of either.

The definitions of each substituent used in the present invention are asfollows.

“C₁-C₆ alkyl” refers to a straight- or branched-chain alkyl group having1 to 6 carbon atom(s), and its example includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl or hexyl, etc., preferably a straight- orbranched-chain alkyl group having 1 to 4 carbon atom(s), more preferablymethyl, ethyl or isopropyl. Preferable examples for R¹, R², R^(2′) andR^(2″) include methyl, ethyl or isopropyl; preferable examples for R³and R⁴ include methyl, ethyl, propyl, isopropyl, butyl or isobutyl; apreferable example for R⁵, R⁶ and R⁷ includes methyl; preferableexamples for R⁸ and R⁹ include methyl or ethyl; preferable examples forR¹⁰ include methyl, ethyl or isopropyl; preferable examples for R¹¹ andR¹² include methyl, ethyl, propyl or isopropyl; preferable examples forR¹³ and R¹⁴ include methyl or ethyl; a preferable example for R¹⁵includes isopropyl; preferable examples for R¹⁶ and R¹⁷ include methylor ethyl; preferable examples for R¹⁸ and R¹⁹ include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl orisopentyl, more preferably ethyl; preferable examples for R²⁰ includemethyl, ethyl, propyl, isopropyl or isobutyl, more preferably ethyl; apreferable example for R²¹ and R²² includes methyl; and preferableexamples for D include ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, sec-pentyl, etc.

Examples of the substituent for “optionally substituted C₁-C₆ alkyl”include halogen, carboxyl, hydroxy, amino, nitro, cyano, C₁-C₆ alkoxy,C₇-C₁₆ aralkyloxy, C₂-C₇ alkoxycarbonyl, C₆-C₁₄ aryl, C₁-C₆ alkylthio,C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylamino, acylaminoand the like, among which hydroxy is preferable. The number of thesubstituents is 1 to 5, preferably 1 to 3.

“C₃-C₇ cycloalkyl” refers to a cycloalkyl having 3 to 7 carbon atoms,specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-methylcyclohexyl or cycloheptyl. Preferable examples thereof include acycloalkyl having 3 to 6 carbon atoms, specifically cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl. More preferable examples thereofinclude cyclopropyl or cyclohexyl. A preferable example for R¹ and R²includes cyclohexyl; a preferable example for R¹⁰ includes cyclohexyl; apreferable example for R¹⁸ and R¹⁹ includes cyclohexyl; a preferableexample for R²⁰ includes cyclohexyl; and preferable examples for ring Cinclude cyclopentyl or cyclohexyl. It is also preferable that R⁸ and R⁹are taken together to form cyclopentyl or cyclohexyl.

“C₁-C₆ alkoxy” refers to a straight- or branched-chain alkoxy grouphaving 1 to 6 carbon atom(s), and its example includes methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy orhexyloxy, etc., preferably an alkoxy having 1 to 4 carbon atom(s), suchas methoxy, ethoxy, isopropoxy, butoxy or tert-butoxy, and morepreferably methoxy or ethoxy. Preferable examples for R¹, R², R^(2′) andR^(2″) include methoxy, isopropoxy or butoxy; preferable examples for R³and R⁴ include methoxy, ethoxy, propoxy or isopropoxy; preferableexamples for R⁵, R⁶ and R⁷ include methoxy or ethoxy; a preferableexample for R¹¹ and R¹² includes methoxy; and preferable examples forR¹⁵ include methoxy, ethoxy, propoxy or isopropoxy.

“Halogen” refers to chlorine, bromine, fluorine or the like. Preferableexamples for R¹ include fluorine or chlorine; preferable examples forR^(2′) and R^(2″) include fluorine, chlorine or bromine; preferableexamples for R³ and R⁴ include chlorine or bromine; and preferableexamples for R⁵, R⁶ and R⁷ include fluorine or chlorine.

“Halo C₁-C₆ alkyl” refers to said C₁-C₆ alkyl substituted with saidhalogen, and its example includes chloromethyl, bromomethyl,fluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl,trichloroethyl, pentafluoropropyl or chlorobutyl, etc., preferablychloromethyl, bromomethyl, fluoromethyl, trifluoromethyl, trifluoroethylor trichloromethyl, and more preferably trifluoromethyl. A preferableexample for R¹, R², R^(2′) and R^(2″) includes trifluoromethyl; apreferable example for R³ and R⁴ includes trifluoromethyl; a preferableexample for R⁵, R⁶ and R⁷ includes trifluoromethyl; preferable examplesfor R¹⁶ and R¹⁷ include trifluoromethyl or trifluoroethyl; andpreferable examples for R¹⁸ and R¹⁹ include trifluoromethyl ortrifluoroethyl.

“Halo C₁-C₆ alkyloxy” refers to, for example, chloromethyloxy,bromomethyloxy, fluoromethyloxy, trifluoromethyloxy, trichloromethyloxy,tribromomethyloxy, trichloroethyloxy, pentafluoropropyloxy orchlorobutyloxy, etc., preferably chloromethyloxy, bromomethyloxy,fluoromethyloxy, trifluoromethyloxy or trichloromethyloxy, and morepreferably trifluoromethyloxy. A preferable example for R¹, R², R^(2′)and R^(2″) includes trifluoromethyloxy.

“C₂-C₁₂ alkoxyalkyl” refers to an alkoxyalkyl of which alkoxy moiety hasthe same meaning as said alkoxy and alkyl moiety has the same meaning assaid alkyl, and its example includes methoxymethyl, ethoxymethyl,propoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl,ethoxyethyl or methoxyethyl, etc. A preferable example for R¹⁸ and R¹⁹includes methoxyethyl.

“C₂-C₇ alkylcarbonyl” refers to acetyl, propionyl, butyryl or pivaloyl,etc., and a preferable example for R²¹ and R²² includes acetyl.

“C₁-C₇ alkylsulfonyl” refers to methanesulfonyl, ethanesulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl or hexylsulfonyl, etc.,and a preferable example for R²¹ and R²² includes methylsulfonyl.

“C₂-C₇ alkoxycarbonyl” refers to an alkoxycarbonyl of which alkyl moietyhas 1 to 6 carbon atom(s) such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl orhexyloxycarbonyl, etc. Preferable examples thereof includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl. Apreferable example for R² includes butoxycarbonyl; a preferable examplefor R⁵, R⁶ and R⁷ includes methoxycarbonyl; a preferable example for R¹³and R¹⁴ includes methoxycarbonyl; and a preferable example for Dincludes ethoxycarbonyl.

“C₁-C₆ acyl” refers to formyl having one carbon atom, or an alkanoylhaving 2 to 6 carbon atoms such as acetyl, propionyl, butyryl orpivaloyl, etc., and its preferable examples include formyl, acetyl orpivaloyl. A preferable example for R² and R^(2″) includes acetyl; apreferable example for R³ includes formyl; a preferable example for R⁵,R⁶ and R⁷ includes acetyl; a preferable example for R¹³ and R¹⁴ includesacetyl; and a preferable example for R²¹ and R²² includes acetyl.

“Alkanediyl” has preferably 1 to 6 carbon atom(s), and its exampleincludes methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl,1,1-dimethylethane-1,2-diyl, 1,1-diethylethane-1,2-diyl,2,2-dimethylethane-1,2-diyl, 2,2-diethylethane-1,2-diyl,1,1-dimethylpropane-1,3-diyl, 1,1-diethylpropane-1,3-diyl,2,2-dimethylpropane-1,3-diyl, 2,2-diethylpropane-1,3-diyl,3,3-dimethylpropane-1,3-diyl or 3,3-diethylpropane-1,3-diyl, etc.Preferable examples for Alk¹ and Alk² include methylene,ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, etc.

“Alkenediyl” has preferably 2 to 6 carbon atom(s), and its exampleincludes ethylene-1,2-diyl, 1-propene-1,3-diyl, 2-propene-1,3-diyl,1-butene-1,4-diyl, 2-butene-1,4-diyl, 3-butene-1,4-diyl or1,3-butadiene-1,4-diyl, etc. Preferable examples for Alk¹ and Alk²include ethylene-1,2-diyl, 1-propene-1,3-diyl, 2-propene-1,3-diyl, etc.

“C₆-C₁₄ aryl” refers to phenyl, naphthyl or biphenyl, etc., preferablyphenyl.

In the “optionally substituted C₆-C₁₄ aryl”, the substituent (s) is/arenot particularly limited, and may be the same or different each otherand is/are arbitrarily positioned. The number of substituents is notparticularly limited so long as they are chemically acceptable, whilethe number is preferably around 1 to 3. Specifically, examples of thesubstituent include C₁-C₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, etc.), hydroxy, C₁-C₆ alkoxy (e.g. methoxy, ethoxy,propoxy, butoxy, etc.), halogen (e.g. fluorine, chlorine, bromine,etc.), nitro, cyano, C₁-C₆ acyl (e.g. formyl, acetyl, propionyl, etc.),C₁-C₆ acyloxy (e.g. formyloxy, acetoxy, propionyloxy, etc.), mercapto,C₁-C₆ alkylthio (e.g. methylthio, ethylthio, propylthio, butylthio,isobutylthio, etc.), amino, C₁-C₆ alkylamino (e.g. methylamino,ethylamino, propylamino, butylamino, etc.), di(C₁-C₆ alkyl)amino (e.g.dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.),carboxyl, C₂-C₇ alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, etc.), amido, trifluoromethyl, C₁-C₆ alkylsulfonyl(e.g. methylsulfonyl, ethylsulfonyl, etc.), aminosulfonyl, C₃-C₇cycloalkyl (e.g. cyclopentyl, cyclohexyl, etc.), phenyl, acylamido (e.g.acetamido, propionylamido, etc.) and the like, among which hydroxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, mercapto, C₁-C₆ alkylthio, halogen,trifluoromethyl, C₁-C₆ acyl, C₂-C₇ alkoxycarbonyl and acylamido arepreferable.

A preferable example for R¹ and R² includes phenyl which may besubstituted with halo C₁-C₆ alkyl (e.g. trifluoromethyl, etc.), C₁-C₆alkyl (e.g. methyl, ethyl, etc.), halogen (e.g. fluorine, chlorine,bromine, etc.), C₁-C₆ alkoxy (e.g. methoxy, etc.), C₁-C₆ acyl (e.g.acetyl, etc.), C₂-C₆ alkenyl (e.g. isopropenyl, etc.) or cyano; apreferable example for R⁵, R⁶ and R⁷ includes phenyl which may besubstituted with halo C₁-C₆ alkyl (e.g. trifluoromethyl, etc.), C₁-C₆alkyl (e.g. methyl, etc.), halogen (e.g. chlorine, etc.) or C₁-C₆ alkoxy(e.g. methoxy, etc.); a preferable example for R⁸ and R⁹ includesphenyl; a preferable example for R¹¹ and R¹² includes phenyl; apreferable example for R¹⁸ and R¹⁹ includes phenyl; a preferable examplefor R⁴³ includes biphenyl; a preferable example for ring A includesphenyl; and preferable examples for ring C include phenyl or naphthyl.

“C₇-C₁₆ aralkyl” refers to an arylalkyl, of which aryl moiety is phenyl(which may be substituted with 1 to 3 substituent(s) mentioned in theabove description of aryl) and alkyl moiety is alkyl having 1 to 6carbon atom(s). Examples thereof include benzyl, phenethyl,phenylpropyl, phenylbutyl or phenylhexyl, etc., among which benzyl orphenylethyl is preferable. A preferable example for R¹ and R² includesbenzyl; a preferable example for R¹¹ and R¹² includes benzyl; and apreferable example for ring C includes benzyl.

“C₆-C₁₄ aryloxy” refers to phenoxy, naphthyloxy, etc. (where the phenylgroup or naphthyl group may be substituted with 1 to 3 substituent(s)mentioned in the above description of aryl), preferably phenoxy. Apreferable example for R¹ and R² includes phenoxy, and a preferableexample for R¹⁵ includes phenoxy.

“C₇-C₁₆ aralkyloxy” refers to an arylalkoxy of which alkoxy moiety has 1to 4 carbon atom(s) (where the aryl group may be substituted with 1 to 3substituent(s) mentioned in the above description of aryl), and examplethereof includes benzyloxy, phenethyloxy, phenylpropyloxy,phenylbutyloxy, etc., preferably benzyloxy. A preferable example for R¹and R² includes benzyloxy; a preferable example for R³ includesbenzyloxy; and a preferable example for R¹⁵ includes benzyloxy.

“C₇-C₁₅ arylcarbonyl” refers to benzoyl, naphthoyl, etc. (where thephenyl group or naphthyl group may be substituted with 1 to 3substituent(s) mentioned in the above description of aryl), preferablybenzoyl. A preferable example for R¹ and R² includes benzoyl.

“C₇-C₁₅ arylcarbonylamino” refers to phenylcarbonylamino,naphthylcarbonylamino, etc. (where the phenyl group or naphthyl groupmay be substituted with 1 to 3 substituent(s) mentioned in the abovedescription of aryl), preferably benzoyl. A preferable example for ringC includes phenylcarbonylamino.

“C₈-C₁₆ aralkylcarbonylamino” refers to benzylcarbonylamino,naphthylcarbonylamino, etc. (where the phenyl group or naphthyl groupmay be substituted with 1 to 3 substituent(s) mentioned in the abovedescription of aryl), preferably benzylcarbonylamino. A preferableexample for ring C includes benzylcarbonylamino.

“heterocycle” refers to a 5- to 6-membered heteroaromatic ring, a 5- to6-membered saturated heterocycle or a 5- to 6-membered unsaturatedheterocycle, any of which contains 1 to 3 heteroatom(s) selected fromnitrogen, oxygen and sulfur as an atom constituting the ring other thancarbon atom, or a fused heterocyclic ring in which said heterocycle andbenzene ring are fused. Specifically, its example includesthiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl,pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl,imidazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, benzothiophen-2-yl,benzothiophen-3-yl, benzofuran-2-yl, benzofuran-3-yl, indol-2-yl,indol-3-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzothiazol-2-yl,benzoxazol-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl,1,3,4-thiadiazol-2-yl, morpholin-4-yl, etc.

A preferable example for R¹ and R² includes thiophen-3-yl; preferableexamples for ring A include imidazol-5-yl, thiazol-5-yl, pyridin-3-yl orpyrrolidin-2-yl; a preferable example for R³ includes thiazol-2-yl; andpreferable examples for ring C include pyridin-2-yl, pyridin-3-yl,thiophen-2-yl, thiophen-3-yl or thiazol-2-yl.

With regard to a substituent in “optionally substituted heterocycle”,the same substituents as those mentioned in the above description ofaryl may be exemplified. The number of substituents is not particularlylimited so long as they are chemically acceptable, while the number ispreferably around 1 to 3.

“C₂-C₆ alkenyl” refers to a straight- or branched-chain alkenyl grouphaving 2 to 6 carbon atoms, and its example includes vinyl, n-propenyl,isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl,n-pentenyl, isopentenyl, neopentenyl, 1-methylpropenyl, n-hexenyl,isohexenyl, 1,1-dimethylbutenyl, 2,2-dimethylbutenyl,3,3-dimethylbutenyl, 3,3-dimethylpropenyl, 2-ethylbutenyl, etc. Apreferable example for R² and R^(2″) includes n-propenyl, and apreferable example for D includes n-propenyl.

“Prodrug” of the compound refers to a derivative of the compound of thepresent invention, which has a group capable of being chemically ormetabolically converted and shows pharmaceutical activity after it ishydrolyzed or solvolyzed or converted under physiological conditions.

For example, there may be listed a derivative in which a substituentsuch as —CO—C₁-C₆ alkyl, —CO₂—C₁-C₆ alkyl, —CONH—C₁-C₆ alkyl, —CO—C₂-C₆alkenyl, —CO₂—C₂-C₆ alkenyl, —CONH—C₂-C₆ alkenyl, —CO—C₆-C₁₄ aryl,—CO₂—C₆-C₁₄ aryl, —CONH—C₆-C₁₄ aryl, —CO-heterocycle, —CO₂-heterocycle,—CONH-heterocycle, etc. (wherein any of said C₁-C₆ alkyl, C₂-C₆ alkenyl,C₆-C₁₄ aryl and heterocycle may be substituted with halogen, C₁-C₆alkyl, hydroxy, C₁-C₆ alkoxy, carboxyl, amino, amino acid residue,—PO₃H₂, —SO₃H, —CO-polyethyleneglycol residue, —CO₂-polyethyleneglycolresidue, —CO-polyethyleneglycol monoalkyl ether residue or—CO₂-polyethyleneglycol monoalkyl ether residue) is attached to thehydroxy group of the compound.

Also, there may be exemplified a derivative in which a substituent suchas —CO—C₁-C₆ alkyl, —CO₂—C₁-C₆ alkyl, —CO—C₂-C₆ alkenyl, —CO₂—C₂-C₆alkenyl, —CO₂—C₆-C₁₄ aryl, —CO—C₆-C₁₄ aryl, —CO-heterocycle,—CO₂-heterocycle, etc. (wherein any of said C₁-C₆ alkyl, C₂-C₆ alkenyl,C₆-C₁₄ aryl and heterocycle may be substituted with halogen, C₁-C₆alkyl, hydroxy, C₁-C₆ alkoxy, carboxyl, amino, amino acid residue,—PO₃H₂, —SO₃H, —CO-polyethyleneglycol residue, —CO₂-polyethyleneglycolresidue, —CO-polyethyleneglycol monoalkyl ether residue,—CO₂-polyethyleneglycol monoalkyl ether residue or —PO₃H₂, etc.) isattached to the amino group of the compound.

Furthermore, there may be exemplified a derivative in which asubstituent such as C₁-C₆ alkoxy, C₆-C₁₄ aryloxy, etc. (wherein saidC₁-C₆ alkoxy or C₆-C₁₄ aryloxy may be substituted with halogen, C₁-C₆alkyl, hydroxy, C₁-C₆ alkoxy, carboxyl, amino, amino acid residue,—PO₃H₂, —SO₃H, polyethyleneglycol residue or polyethyleneglycolmonoalkyl ether residue, etc.) is attached to the carboxyl group of thecompound.

“Pharmaceutically acceptable salt” includes various inorganic acidaddition salts such as hydrochloride, hydrobromide, sulphate, phosphateor nitrate, etc.; various organic acid addition salts such as acetate,propionate, succinate, glycolate, lactate, malate, oxalate, tartrate,citrate, maleate, fumarate, methanesulfonate, benzensulfonate,p-toluenesulfonate or ascorbate, etc.; or various salts with an aminoacid such as aspartate or glutamate, etc., although it is not limitedthereto. It may be hydrated compound, hydrate or solvate depending onthe circumstances.

“MTP in the small intestine” refers to the MTP existing in smallintestinal epithelial cells.

“MTP in the liver” refers to the MTP existing in hepatic cells.

The expression “selectively inhibit MTP in the small intestine” meansthe level of inhibition is at least about 5 times higher, preferablyabout 10 times higher, than MTP inhibition in other parts of body suchas liver and heart, especially liver. To be more specific, on the basisof S9 metabolic stability test, it means that in the test using human orhamster S9 the remaining rate of unaltered form 10 minutes after thetreatment with small intestine S9 is about 10 times or more higher thanthat in the case of the treatment with liver S9 (see Test Example 7).

The expression “it is metabolized to the amount at which the remainingMTP inhibitor in the liver does not substantially inhibit the MTP in theliver” means that almost all of the orally administered MTP inhibitorsare metabolized to an inactive metabolite before arriving at the liveror at the moment of arriving at the liver and show substantially no MTPinhibitory activity in the liver, i.e. the MTP inhibitors are convertedto those that do not substantially inhibit TG release from the liver.More specifically, it means the condition where TG-releasing activity ofthe liver is kept at the level of about 80% or more, preferably about90% or more, more preferably 100% of the normal level. In terms ofmetabolism, it means that the ratio of inactive metabolite to unalteredform in portal vein blood is approximately 8 or more to 1 one hour afterthe oral administration to hamsters, i.e. about 80% or more of the agent(compound) is metabolized before arriving at the liver (see Test Example6), or on the basis of liver S9 metabolic stability test, it means that10 minutes after the test using human or hamster S9 the remaining rateof unaltered form is about 20% or less, preferably about 10% or less,more preferably about 8% or less (see Test Example 7).

The expression “MTP inhibitor does not substantially inhibit MTP in theliver” has essentially the same meaning with the above “it ismetabolized to the amount at which the remaining MTP inhibitor in theliver does not substantially inhibit the MTP in the liver”, and meansthe condition where TG-releasing activity of the liver is kept at thelevel of about 80% or more, preferably about 90% or more, morepreferably 100% of the normal level.

As “pharmaceutically acceptable carrier”, various organic or inorganiccarrier materials which are conventionally used as formulation materialare used, and it is formulated as excipient, lubricant, binder,disintegrating agent, solvent, solubilizer, suspending agent,isotonizing agent, buffer, soothing agent, etc. If desired,pharmaceutical additives such as preservative, antioxidant, coloringagent, sweetening agent, etc. may be also used. Preferable examples ofsaid excipient include lactose, sucrose, D-mannitol, starch, crystallinecellulose, light anhydrous silicic acid, etc. Preferable examples ofsaid lubricant include magnesium stearate, calcium stearate, talc,colloidal silica, etc. Preferable examples of said binder includecrystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc.Preferable examples of said disintegrating agent include starch,carboxymethylcellulose, carboxymethylcellulose calcium, crosscarmellosesodium, sodium carboxymethylstarch, etc. Preferable examples of saidsolvent include water for injection, alcohol, propylene glycol,macrogol, sesame-seed oil, corn oil, propylene glycol fatty acid ester,etc. Preferable examples of said solubilizer include polyethyleneglycol,propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.Preferable examples of said suspending agent include surfactants (e.g.stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate, etc), polyvinyl alcohol, polyvinylpyrrolidone,carboxymethylcellulose sodium, methylcellulose, hydroxymethyl cellulose,etc. Preferable examples of said isotonizing agent include sodiumchloride, glycerin, D-mannitol, etc. Preferable examples of said bufferinclude phosphate, acetate, carbonate, citrate, etc. Preferable examplesof said soothing agent include benzyl alcohol, etc. Preferable examplesof said preservative include paraoxybenzoic acid esters, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.Preferable examples of said antioxidant include sulfites, ascorbic acid,etc. Preferable examples of said sweetening agent include aspartame,saccharin sodium, stevia, etc. Preferable examples of said coloringagent include food colors such as food yellow No. 5, food red No. 2 andfood blue No. 2, lake colors for food, iron oxide, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

Detailed description is given below with respect to varioussubstituents.

R¹ is preferably hydrogen; C₁-C₆ alkyl such as methyl, ethyl, etc.;C₁-C₆ alkoxy such as methoxy, isopropoxy, etc.; halogen such asfluorine, chlorine, etc.; halo C₁-C₆ alkyl such as trifluoromethyl,etc.; or C₂-C₆ alkenyl such as isopropenyl, etc.

R² is preferably phenyl (which may be substituted with halo C₁-C₆ alkylsuch as trifluoromethymethyl, etc.; C₁-C₆ alkyl such as methyl, ethyl,etc.; halogen such as fluoro, chlorine, bromine, etc.; C₁-C₆ alkoxy suchas methoxy, etc.; C₁-C₆ acyl such as acetyl, etc.; C₂-C₆ alkenyl such asisopropenyl, etc.; or cyano); C₁-C₆ alkyl such as ethyl, isopropyl,etc.; C₃-C₇ cycloalkyl such as cyclohexyl, etc.; C₁-C₆ alkoxy such asbutoxy, etc.; halo C₁-C₆ alkyl such as trifluoromethyl, etc.; halo C₁-C₆alkyloxy such as trifluoromethoxy, etc.; C₇-C₁₆ aralkyl such as benzyl,etc.; C₆-C₁₄ aryloxy such as phenoxy (of which aryl moiety may besubstituted with halo C₁-C₆ alkyl such as trifluoromethyl, etc.), etc.;C₇-C₁₅ arylcarbonyl such as benzoyl (of which aryl moiety may besubstituted with halogen such as chlorine, etc.), etc.; heterocycle suchas thiophen-3-yl, etc.; C₂-C₇ alkoxycarbonyl such as butoxycarbonyl,etc.; —N(R⁴⁰)(R⁴¹) (wherein R⁴⁰ and R⁴¹ are each independently hydrogenor optionally substituted phenyl).

R^(2′) is preferably hydrogen or halogen such as chlorine, etc.

R^(2″) is preferably hydrogen, halo C₁-C₆ alkyl such as trifluoromethyl,etc.; C₁-C₆ alkyl such as methyl, ethyl, etc.; halogen such as fluorine,chlorine, bromine, etc.; C₁-C₆ alkoxy such as methoxy, etc.; C₁-C₆ acylsuch as methylcarbonyl, etc.; C₂-C₆ alkenyl such as isopropenyl, etc.;or cyano.

Ring A is preferably

among which phenyl is especially preferred.

X is preferably —COO—, —N(R¹⁰)CO— or —CON(R¹⁰)— (wherein R¹⁰ ishydrogen; C₁-C₆ alkyl such as methyl, isopropyl, etc.; or C₃-C₇cycloalkyl such as cyclohexyl, etc.), among which —COO— or —CONH— isespecially preferred.

Ring B is preferably

or more preferably

or most preferably

R³ is preferably hydrogen; hydroxy; halogen such as chlorine, bromine,etc.; C₁-C₆ alkyl such as methyl, ethyl, isopropyl, isobutyl, etc.;substituted C₁-C₆ alkyl such as isobutyl substituted with hydroxy, etc.;C₁-C₆ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, etc.; haloC₁-C₆ alkyl such as trifluoromethyl, etc.; C₇-C₁₆ aralkyloxy such asbenzyloxy, etc.; C₁-C₆ acyl such as formyl, etc.; optionally substitutedheterocycle such as 4-methyl-thiazol-2-yl, etc.; —CON(R¹¹)(R¹²) (whereinR¹¹ and R¹² are each independently hydrogen; C₁-C₆ alkyl such as methyl,ethyl, propyl, isopropyl, etc.; C₆-C₁₄ aryl such as phenyl, etc.; C₇-C₁₆aralkyl such as benzyl, etc.; C₁-C₆ alkoxy such as methoxy, etc.; or R¹¹and R¹² may be taken together with the nitrogen to form

(wherein p is an integer of 0 or 1)); —N(R¹³)(R¹⁴) or —CH₂—N(R¹³)(R¹⁴)(wherein R¹³ and R¹⁴ are each independently hydrogen; C₁-C₆ alkyl suchas methyl, ethyl, etc.; C₂-C₇ alkoxycarbonyl such as methoxycarbonyl,etc.; C₁-C₆ acyl such as acetyl, etc.; or R¹³ and R¹⁴ may be takentogether with the nitrogen to which they are attached to form

(wherein p has the same meaning as defined above)); or —CO(R¹⁵) (whereinR¹⁵ is C₁-C₆ alkyl such as isopropyl, etc.; C₁-C₆ alkoxy such asmethoxy, ethoxy, propoxy, isopropoxy, etc.; C₇-C₁₆ aralkyloxy such asbenzyloxy, etc.; or hydroxy). Alternatively, R³ and R¹⁰ may be takentogether with the nitrogen to which R¹⁰ is attached and ring B to form

R⁴ is preferably hydrogen or halogen such as fluorine, chlorine,bromine, etc.

Alk1¹ is preferably methylene or ethane-1,1-diyl.

l is preferably 0, 1 or 2.

Alk1² is preferably methylene.

m is preferably 0 or an integer of 1 to 3.

D is preferably C₁-C₆ alkyl such as ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, sec-pentyl, etc.; C₂-C₆ alkenyl such as n-propenyl,etc.; C₂-C₇ alkoxycarbonyl such as ethoxycarbonyl, etc.; —N(R⁴²)—CO(R⁴³)(wherein R⁴² is hydrogen or C₁C₆ alkyl; R⁴³ is C₆-C₁₄ aryl such asbiphenyl, etc.; or C₇-C₁₆ aralkyl); or a group of the formula shownbelow:

(wherein ring C, R⁵, R⁶ and R⁷ each has the same meaning as definedabove).

Ring C is preferably C₆-C₁₄ aryl such as phenyl, naphthyl, etc.; C₃-C₇cycloalkyl such as cyclopentyl, cyclohexyl, etc.; C₇-C₁₆ aralkyl such asbenzyl, etc.; or heterocycle such as pyridine-3-yl, thiophen-3-yl,thiazol-2-yl, etc. Alternatively, ring C may be take together with R⁷and R⁸ to form

R⁵ is preferably hydrogen; C₁-C₆ alkyl such as methyl, etc.; C₁-C₆alkoxy such as methoxy, etc.; halogen such as chlorine, etc.; nitro;amino; C₆-C₁₄ aryl such as phenyl, etc.; or —CON(R¹⁶)(R¹⁷) or—CH₂—CON(R¹⁶)(R¹⁷) (wherein R¹⁶ and R¹⁷ are each independently hydrogen;C₁-C₆ alkyl such as ethyl, etc., or halo-C₁-C₆ alkyl such as2,2,2-trifluoroethyl, etc.).

R⁶ is preferably hydrogen or halogen such as chlorine, etc.

R⁷ is preferably hydrogen.

R⁸ and R⁹ are each independently preferably hydrogen; C₁-C₆ alkyl suchas ethyl, etc.; C₆-C₁₄ aryl such as phenyl, etc.; hydroxy-C₁-C₆ alkylsuch as hydroxymethyl, etc.; —CON(R¹⁸)(R¹⁹) (wherein R¹⁸ and R¹⁹ areeach independently hydrogen; C₁-C₆ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, etc.; C₃-C₇ cycloalkyl such as cyclohexyl,etc.; halo C₁-C₆ alkyl such as 2,2,2-trifluoroethyl, etc.; C₂-C₁₂alkoxyalkyl such as methoxyethyl, etc.; or C₆-C₁₄ aryl such as phenyl,etc.); —COO(R²⁰) or —(CH₂)_(n)—OCO(R²⁰) (wherein R²⁰ is hydrogen; C₁-C₆alkyl such as methyl, ethyl, propyl, isopropyl, isobutyl, etc.; or C₃-C₇cycloalkyl such as cyclohexyl, etc., and n is an integer of 0 or 1);—N(R²¹)(R²²) (wherein R²¹ and R²² are each independently hydrogen; C₁-C₆alkyl such as methyl, isopropyl, etc.; C₁-C₆ acyl such as acetyl,propionyl, butyryl, etc.; C₁-C₆ alkylsulfonyl such as methylsulfonyl,etc.; or R²¹ and R²² may be taken together with the nitrogen atom towhich they are attached to form

or R⁸ and R⁹ taken together may form C₃-C₇ cycloalkyl such ascyclopropyl, cyclohexyl, etc.

Preferred embodiments of various substituents and the substitution sitewill be illustrated below.

R¹ is preferably hydrogen, halo C₁-C₆ alkyl or C₁-C₆ alkyl, among whichhydrogen is especially preferred.

R² is preferably phenyl (which may be substituted with halo C₁-C₆ alkylsuch as trifluoromethyl, etc.; C₁-C₆ alkyl such as methyl, etc.; halogensuch as chlorine, etc.; or C₁-C₆ alkoxy such as methoxy, etc.).

R^(2′) is preferably hydrogen.

R^(2″) is preferably hydrogen, halo-C₁-C₆ alkyl, halogen, C₁-C₆ alkyl orC₁-C₆ alkoxy, and trifluoromethyl is especially preferred.

X is preferably —COO— or —CON(R¹⁰)— (R¹⁰ has the same meaning as definedabove), among which —CONH— is especially preferred.

Ring B is preferably phenyl.

R³ is preferably C₁-C₆ alkyl, C₁-C₆ alkoxy, —CON(R¹¹)(R¹²) (wherein R¹¹and R¹² are each independently preferably hydrogen or C₁-C₆ alkyl) or—CO(R¹⁵) (wherein R¹⁵ is preferably C₁-C₆ alkoxy).

R⁴ is preferably hydrogen or methyl, and especially preferably methyl.

Alk¹ is preferably methylene.

Alk² is preferably methylene.

l is preferably 0 or 1, especially 1.

m is preferably 1 or 2, especially 1 or 2.

D is preferably C₁-C₆ alkyl or a group of the formula shown below:

(wherein ring C, R⁵, R⁶ and R⁷ each has the same meaning as definedabove).

Ring C is preferably phenyl, pyridin-3-yl, thiophen-3-yl, thiophen-2-yland thiazol-2-yl, among which phenyl is especially preferred.

R⁵, R⁶ and R⁷ each is preferably hydrogen, halogen or C₁-C₆ alkyl, amongwhich hydrogen is especially preferred.

R⁸ and R⁹ each is preferably hydrogen, C₁-C₆ alkyl, C₆-C₁₄ aryl,—CON(R¹⁸)(R¹⁹) (wherein R¹⁸ and R¹⁹ each is preferably hydrogen or C₁-C₆alkyl) or —COO(R²⁰)(wherein R²⁰ is preferably hydrogen or C₁-C₆ alkyl),among which —CON(R¹⁸)(R¹⁹) (wherein R¹⁸ and R¹⁹ each is preferablyhydrogen or C₁-C₆ alkyl) or —COO(R²⁰) (wherein R²⁰ is preferablyhydrogen or C₁-C₆ alkyl) are more preferred, and —COO(R²⁰) (wherein R²⁰is preferably C₁-C₆ alkyl) is especially preferred.

The substitution site of —(CH₂)₁— on the benzene ring in the formula(1′) is preferably i-position.

The compounds of the present invention may include hydrates or solvates,depending on the case, and may further include their metabolites.Furthermore, the compounds of the present invention include racematesand optically active compounds. The optically active compounds arepreferably those wherein one of enantiomers is in enantiomer excess ofabout 90% or higher, more preferably in enantiomer excess of about 99%or higher.

When the compounds of the present invention are used as an agent for thetreatment or prophylaxis of hyperlipidemia or arteriosclerosis, they canbe administered systemically or locally, and orally or parenterally.Though the dose may vary depending on the age, body weight, symptoms,therapeutic effect, etc., the daily dose per adult is in the range of0.1 mg to 1 g per one dose and can be administered one to several timesper day. Also, the compounds of the present invention can beadministered to human beings as well as animals other than human beings,especially mammals, for the treatment or prevention of said diseases.The compounds of the present invention can be used in the same way forthe treatment or prevention of coronary artery diseases, obesity,diabetes or hypertension.

In the formulation of the compounds of the present invention into solidcompositions and liquid compositions for oral administration orinjections, etc., for parenteral administration, there may be addedappropriate additives such as diluents, dispersants, adsorbents,solubilizers, etc. In addition, the composition of the present inventionmay take the known form such as tablets, pills, powders, granules,suppositories, injections, eye drops, solutions, capsules, troches,aerosols, elixirs, suspensions, emulsions, syrups, etc.

When the compounds of the present invention are formulated into solidpreparations such as tablets, pills, powders, granules, etc., examplesof such an additive include lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone,magnesium aluminometasilicate or powdery silicic anhydride. In the casewhere the compounds of the present invention are formulated into tabletsor pills, they may be coated with a gastroenteric or enteric coatingfilm containing a substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxymethyl cellulose phthalate. Furthermore, the tabletsor pills may be multi-layered tablets comprising two or more layers.

As the pharmaceutical compositions of the present invention, there arealso exemplified capsules in which are filled liquid, semi-solid orsolid contents prepared by dissolving the compounds of the presentinvention in a solvent and adding an additive thereto. Examples of saidsolvents are purified water, ethanol, vegetable oil, etc., among whichethanol or a mixture of purified water and ethanol is preferably used.Any additives commonly used in the preparation of capsules can be usedwithout any particular limitation. Such additives include, for example,propylene glycol fatty acid esters; low molecular weight polyethyleneglycols such as polyethylene glycol 200 to 600, etc., glycerine fattyacid esters thereof, and medium chain fatty acid triglycerides thereof;alcohols/polyols such as stearyl alcohol, cetanol, polyethylene glycol,etc., or esters thereof; lipids such as sesame oil, soy bean oil, peanutoil, corn oil, hydrogenated oil, paraffin oil, bleached wax; fatty acidssuch as triethyl citrate, triacetin, stearic acid, palmitic acid,myristic acid, etc., and derivatives thereof. These additives aresuitable for preparing liquid or semi-solid contents. In the capsules ofthe present invention, propylene glycol fatty acid esters are preferableas such an additive. Examples of the propylene glycol fatty acid estersare propylene glycol monocaprylate (Capmul PG-8 (Brand name), Sefol 218(Brand name), Capryo 190 (Brand name), propylene glycol monolaurate(Lauroglycol FCC (Brand name), propylene glycol monooleate (Myverol P-O6(Brand name)), propylene glycol myristate, propylene glycolmonostearate, propylene glycol lisinolate (Propymuls (Brand name)),propylene glycol dicaprylate/dicaprate (Captex (Trademark) 200 (Brandname)) propylene glycol dilaurate, propylene glycol distearate andpropylene glycol dioctanoate (Captex (Trademark) 800 (Brand name)).Although there is no particular limitation to the materials constitutingthe capsules of the present invention, they include, for example,polysaccharides derived from natural products such as agar, alginic acidsalt, starch, xanthan, dextran, etc; proteins such as gelatin, casein,etc.; chemically processed products such as hydroxystarch, pullulan,hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylalcohol or derivatives thereof, polyacryl derivatives,polyvinylpyrrolidone or derivatives thereof, polyethylene glycol, etc.

In the case where the pharmaceutical compositions of the presentinvention are liquid formulations for oral administration such aspharmaceutically acceptable emulsions, solubilizers, suspensions, syrupsor elixirs, etc., diluents to be used include, for example, purifiedwater, ethanol, vegetable oils, emulsifiers, etc. In addition to suchdiluents, auxiliary agents such as wetting agents, suspending agents,sweeteners, condiments, flavors or antiseptics may be added to saidliquid formulations.

In the case where the pharmaceutical compositions of the presentinvention are parenteral formulations such as injections, there areemployed sterilized aqueous or non-aqueous solutions, solubilizers,suspending agents, emulsifiers, etc. Examples of the aqueous solutions,solubilizers and suspending agents include distilled water forinjections, physiological saline, cyclodextrin, and derivatives thereof;organic amines such as triethanolamine, diethanolamine,monoethanolamine, triethylamine, etc.; and inorganic alkaline solutions.When aqueous solutions are employed, for example, propylene glycol,polyethylene glycol or vegetable oils such as olive oil, or alcoholssuch as ethanol may be further added. Further, surfactants (for mixedmicelle formation) such as polyoxyethylene hydrogenated castor oils,sucrose fatty acid esters, or lecithin or hydrogenated lecithin (forliposome formation), etc. can be used as a solubilizer. Furthermore,with regard to the parenteral formulations of the present invention,they may be formulated into emulsions comprising non-aqueoussolubilizers such as vegetable oils, together with lecithin,polyoxyethylene hydrogenated castor oil orpolyoxyethylene-polyoxypropylene glycol, etc.

Further, the present invention provides a novel agent for the treatmentor prophylaxis of hyperlipidemia, arteriosclerosis, coronary arterydiseases, obesity, diabetes or hypertension with new functions that havenever been known before. The agents of the present invention for thetreatment or prevention of said diseases are characterized in that theyselectively inhibit MTP (microsomal triglyceride transfer protein) inthe small intestine. Among these agents, an agent which does notsubstantially inhibit MTP in the liver, while inhibits only MTP in thesmall intestine is desirable. Specifically, it is preferable that MTPinhibition of the agent in the liver is approximately ⅓ or less,preferably 1/100 or less when compared to that in the small intestine asestimated in terms of ED₅₀ or ED₂₀. As one preferred embodiment of thetherapeutic or prophylactic agents of the present invention for saiddiseases, they inhibit MTP in the small intestine, and they are thenmetabolized in the small intestine, blood, and liver to the amount atwhich the residual agent arriving at the liver does not substantiallyinhibit MTP in the liver. It is particularly preferable that, when 300mg/kg of the compound of the present invention is administered orally,the rate of liver TG release inhibition exerted by the residual compoundreaching the liver is about 20% or less, preferably less than about 10%,more preferably about 0%. Specifically, it is desirable that the agenthas about 40% or less, preferably about 20% or less inhibition rate ofliver TG release when assayed by the method of Test Example 4 which willbe hereinafter mentioned.

The pharmaceutical compositions or agents of the present invention canbe used in combination with other pharmaceutical compositions or agents.As other agents, there may be exemplified drugs for the treatment orprophylaxis of hyperlipidemia, arteriosclerosis, coronary arterydisease, obesity, diabetes, or hypertension, and they can be used solelyor in combination with two or more kinds of said drugs. Examples of theantihyperlipidemic drugs include a statin-type drug, more specifically,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin orcerivastatin. Examples of the anti-obesity drugs include mazindol orolristat. Examples of the anti-diabetic drugs include insulinpreparations, sulfonylurea drugs, insulin secretion-promotor drugs,sulfonamide drugs, biguanide drugs, α-glucosidase inhibitors, insulinresistance-improving drugs, etc., more specifically insulin,glibenclamid, tolbutamide, glyclopyramide, acetohexamide, glimepiride,tolazamide, gliclazide, nateglinide, glibuzol, metformin hydrochloride,buformin hydrochloride, voglibose, acarbose, pioglitazone hydrochloride,etc. Examples of the anti-hypertension drugs include loop diuretics,angiotensin converting enzyme inhibitors, angiotensin II receptorantagonists, Calcium antagonists, β-blockers, α,β-blockers andα-blockers, and more specifically, furosemide delayed release,captopril, captopril delayed release, enalapril maleate, alacepril,delapril hydrochloride, silazapril, lisinopril, benazeprilhydrochloride, imidapril hydrochloride, temocapril hydrochloride,quinapril hydrochloride, trandolapril, perindopril erbumine, losartanpotassium, candesartan cilexetil, nicardipine hydrochloride, nicardipinehydrochloride delayed release, nilvadipine, nifedipine, nifedipinedelayed release, benidipine hydrochloride, diltiazem hydrochloride,diltiazem hydrochloride delayed release, nisoldipine, nitrendipine,manidipine hydrochloride, barnidipine hydrochloride, efonidipinehydrochloride, amlodipine besylate, felodipine, cilnidipine,aranidipine, propranolol hydrochloride, propranolol hydrochloridedelayed release, pindolol, pindolol delayed release, indenololhydrochloride, carteolol hydrochloride, carteolol hydrochloride delayedrelease, bunitrolol hydrochloride, bunitrolol hydrochloride delayedrelease, atenolol, asebutolol hydrochloride, metoprolol tartrate,metoprolol tartrate delayed release, nipradilol, penbutolol sulfate,tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxololhydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantololhydrochloride, labetalol hydrochloride, arotinolol hydrochloride,amosulalol hydrochloride, prazosin hydrochloride, terazosinhydrochloride, doxazosin mesylate, bunazocin hydrochloride, bunazocinhydrochloride delayed release, urapidil, and phentolamine mesylate, etc.

There is no particular limitation to the timing for the administrationof pharmaceutical compositions or agents and other drugs for combinationuse according to the present invention, and they may be administeredsimultaneously or intermittently.

The amount of such drugs for combination use can be determined based ontheir clinical doses, and can be chosen depending on the age, weight,condition, medication time, dosage form, method of administration,combination, etc. There is no particular limitation to the dosage formof the drugs for combination use, and it may be sufficient that thepharmaceutical compositions or agents and other drugs for combinationuse according to the present invention are combined at the time ofadministration.

Next, a process for preparing an ester compound represented by theformula (1) will be illustrated below as an example, but the process ofthe present invention is not limited thereto. In the process mentionedbelow, D is a group of the formula (2):

(wherein ring C, R⁵, R⁶ and R⁷ each has the same meaning as definedabove), and when D is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₇ alkoxycarbonylor —N(R⁴²)—CO(R⁴³) (R⁴² and R⁴³ each has the same meaning as definedabove), the compound can be prepared in the same.

In addition, the functional groups other than those to be reacted may beoptionally protected in a previous stage and may be deprotected in anappropriate stage.

Further, the reaction in each step may be carried out in the usualmanner, and separation and purification may be conducted by theappropriate selection or combination of conventional methods such ascrystallization, recrystallization, column chromatography, preparativeHPLC, etc.

Process 1

Among the compounds represented by the formula (1), a process forpreparing compounds in which X is —CONH—(CH₂)_(n)— will be illustratedbelow.

In the above reaction scheme, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, l, m,n, Alk¹, Alk², ring A, ring B, and ring C each has the same meaning asdefined above and R²³ is C₁-C₆ alkyl.

Step 1-1

A carboxylic acid of the formula (2) is reacted with oxalyl chloride orthionyl chloride in a solvent to give an acid chloride of the formula(3).

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and esters such as ethylacetate, methyl acetate, butyl acetate, etc., and they may be usedsolely or in combination thereof. Preferred solvents in the presentreaction include methylene chloride, chloroform or toluene, all of whichcontain a catalytic amount of N,N-dimethylformamide.

The reaction temperature is about −20° C. to 120° C., preferably about0° C. to room temperature.

The reaction time is about 10 minutes to 8 hours, preferably about 30minutes to 4 hours.

Step 1-2

This step is a general reduction process for the nitro group attacheddirectly to the aromatic ring. A nitro compound of the formula (4) ishydrogenated in a solvent in the presence of a catalyst to give acompound of the formula (5).

The solvent used in the reaction includes, for example, ethers such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.; alcohols such asmethanol, ethanol, isopropyl alcohol, t-butanol, etc.; and esters suchas ethyl acetate, methyl acetate, butyl acetate, etc.; and they are usedsolely or in combination thereof. Preferred solvents in the presentreaction include alcohols such as methanol, ethanol, isopropyl alcohol,t-butanol, etc., and a mixture of said alcohol solvent andtetrahydrofuran and/or water.

The catalyst used in the reaction includes, for example,palladium-carbon, palladium hydroxide, Raney-Ni, platinum oxide, andamong which palladium-carbon or reduced iron is preferred.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 100° C.

The reaction time is about 30 minutes to 8 days, preferably about onehour to 96 hours.

Step 1-3

This step is a general condensation reaction between acid chlorides andamines. An acid chloride of the formula (3) is condensed with an amineof the formula (5) in a solvent in the presence of a base to give acompound of the formula (6).

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and esters such as ethylacetate, methyl acetate, butyl acetate, etc., and they can be usedsolely or in combination thereof. Preferred solvents in the presentreaction include methylene chloride, chloroform, toluene, ethyl acetateor tetrahydrofuran.

Examples of the bases used in the present invention include organicbases such as triethylamine, pyridine, N-methylmorpholine, etc.; alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, etc.; and alkali metal carbonates such as sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.,among which triethylamine, sodium hydroxide or sodium bicarbonate ispreferable.

The reaction temperature is about 0° C. to 80° C., preferably about 0°C. to room temperature.

The reaction time is about 10 minutes to 48 hours, preferably about 30minutes to 24 hours.

In the case of a compound of the formula (5) wherein R²³ is hydrogen, acompound of the formula (7) can be prepared by one step of condensationbetween an aminocarboxylic acid and an acid chloride (Schotten-Baumannreaction).

Alternatively, a compound of the formula (6) can be prepared by using acondensing agent (e.g. WSC-HOBT, DCC-HOBT) for a compound of the formula(2) and a compound of the formula (5). Further, a compound of theformula (6) may be provided by converting a compound of the formula (2)into its mixed anhydride, followed by the reaction in the presence of abase.

Step 1-4

This step is a general ester hydrolysis reaction using alkali. Acompound of the formula (6) is hydrolysed in a solvent in the presenceof a base to give a compound of the formula (7).

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; and alcohols such as methanol, ethanol, isopropyl alcohol, etc.;and they can be used solely or in combination thereof. Preferredsolvents in the present reaction include a mixture of tetrahydrofuranand ethanol or methanol. Examples of the bases are aqueous solutions ofalkali metal carbonates such as sodium carbonate, potassium carbonate,etc., or aqueous solutions of alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, etc., among whichsodium hydroxide or lithium hydroxide is preferable.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 80° C.

The reaction time is about 1 hour to 24 hours, preferably about 2.5hours to 12 hours.

Step 1-5

This step is a general condensation reaction of a carboxylic acid withan alcohol.

A carboxylic acid of the formula (7) is condensed with an alcohol of theformula (8) in a solvent in the presence of a base and a condensingagent to give a compound of the formula (1-1) which is one of theobjective compounds.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; esters such as ethyl acetate,methyl acetate, butyl acetate, etc.; polar solvents such as acetone,N,N-dimethylformamide, dimethyl sulfoxide, etc.; and they can be usedsolely or in combination thereof. Preferred solvents in the presentreaction include tetrahydrofuran, acetone, methylene chloride orN,N-dimethylformamide.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which dimethylaminopyridine is preferred.

Examples of the condensing agents used in the reaction include1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),dicyclohexylcarbodiimide (DCC), etc. among which1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride ispreferred.

The reaction temperature is about 0° C. to 80° C., preferably about 0°C. to room temperature.

The reaction time is about 1 hour to 48 hours, preferably about 3 hoursto 24 hours.

As an alternative process, a carboxylic acid of the formula (7) may beconverted into its mixed anhydride and then reacted with an alcohol ofthe formula (8) in the presence of a base.

Process 1a

Process 1a as shown below is an alternative of Process 1.

In the above reaction scheme, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R²³,l, m, n, Alk¹, Alk², ring A, ring B and ring C each has the same meaningas defined above.

Step 1a-1

A compound of the formula (105) can be prepared from a compound of theformula (4) in a similar manner to Step 1-4 of Process 1.

Step 1a-2

A compound of the formula (106) can be prepared by condensing acarboxylic acid of the formula (105) with an alcohol of the formula (8)in a similar manner to Step 1-5 of Process 1.

Step 1a-3

A compound of the formula (107) can be prepared from a compound of theformula (106) in a similar manner to Step 1-2 of Process 1.

Step 1a-4

A compound of the formula (1-1) which is one of the objective compoundscan be prepared by condensing an amine of the formula (107) with an acidchloride of the formula (3) in a similar manner to Step 1-3 of Process1.

Process 2

Among the compounds represented by the formula (1), a process forpreparing compounds in which X is —COO— (CH₂)_(n)— will be illustratedbelow.

In the above reaction scheme, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, l, m,n, Alk¹, Alk², ring A, ring B and ring C each has the same meaning asdefined above, and R²⁴ is a hydroxy-protecting group (for example,benzyl, p-methoxybenzyl, tert-butyl, trialkylsilyl, etc.).

Step 2-1

This step is a condensation reaction of a carboxylic acid with analcohol similar to Step 1-5 of Process 1. A compound of the formula (10)can be prepared by condensing a carboxylic acid of the formula (9) withan alcohol of the formula (8) in a solvent in the presence of a base anda condensing agent.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; esters such as ethyl acetate,methyl acetate, butyl acetate, etc.; polar solvents such as acetone,N,N-dimethylformamide, dimethyl sulfoxide, water, etc.; and they can beused solely or in combination thereof. Preferred solvents in the presentreaction include tetrahydrofuran, methylene chloride orN,N-dimethylformamide.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which dimethylaminopyridine is preferred.

Examples of the condensing agents used in the reaction include1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),dicyclohexylcarbodiimide (DCC), etc., among which1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride ispreferred.

The reaction temperature is about 0° C. to 80° C., preferably about 0°C. to room temperature.

The reaction time is about 2 hours to 48 hours, preferably about 6 hoursto 24 hours.

Step 2-2

This step is a general deprotection method for hydroxy groups. Forexample, when R²⁴ is benzyl in a compound of the formula (10), thecompound of the formula (10) is hydrogenated in a solvent in thepresence of a catalyst to give a compound of the formula (11).

The solvent used in the reaction includes, for example, ethers such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; alcoholssuch as methanol, ethanol, isopropyl alcohol, t-butanol, etc.; andesters such as ethyl acetate, methyl acetate, butyl acetate, etc.; andthey can be used solely or in combination thereof. Preferred solvents inthe present reaction are alcohols such as methanol, ethanol, isopropylalcohol, t-butanol, etc.

Examples of the catalyst used in the reaction include palladium carbon,palladium hydroxide, Raney-Ni, platinum oxide, etc., among whichpalladium carbon is preferred.

The reaction temperature is about 0° C. to 80° C., preferably about 0°C. to room temperature.

The reaction time is about 1 hour to 16 hours, preferably about 2 hoursto 8 hours.

Step 2-3

This step is a condensation reaction between a carboxylic acid and analcohol similar to Step 1-5 of Process 1. A compound of the formula (11)is condensed with an alcohol of the formula (2) in a solvent in thepresence of a base and a condensing agent to give a compound of theformula (1-2) which is one of the objective compounds.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; esters such as ethyl acetate,methyl acetate, butyl acetate, etc.; and polar solvents such as acetone,N,N-dimethylformamide, dimethyl sulfoxide, etc., and they can be usedsolely or in combination thereof. Preferred solvents in the presentreaction are tetrahydrofuran, methylene chloride, dimethylformamide,etc.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which dimethylaminopyridine is preferred.

Examples of the condensing agents used in the reaction include1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl),dicyclohexylcarbodiimide (DCC), etc., among which1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride ispreferred.

The reaction temperature is about 0° C. to 80° C., preferably about 0°C. to room temperature.

The reaction time is about 2 hours to 48 hours, preferably about 6 hoursto 24 hours.

As an alternative process of Process 2, a phenol or an alcoholderivative derived from a compound of the formula (9) (wherein R²⁴ isp-methoxybenzyl and the carboxyl group is protected by benzyl ester) issubjected to removal of the p-methoxybenzyl group with2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), etc., followed bycondensation with a compound of the formula (2). After removal of thebenzyl group from the resulting compound, the deprotected compound iscondensed with a compound of the formula (8) to give a compound of theformula (1-2) which is one of the objective compounds.

Process A

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R⁴ has the same meaning as defined above, R³¹ is C₁-C₆ alkyl,and 1′ is 1).

In the above reaction scheme, R³¹ and R⁴ each has the same meaning asdefined above, R²⁵ is C₁₋₆ alkyl, X₂ and X₃ each is halogen, and Et isethyl.

Step A-1

A compound of the formula (14) can be prepared by reacting a compound ofthe formula (12) with a malonic acid ester of the formula (13) in asolvent in the presence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;alcohols such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.;and polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,etc., and they can be used solely or in combination thereof. A preferredsolvent in the present reaction is N,N-dimethylformamide.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; alkali metal alkoxidessuch as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.;alkali metal amides such as sodium amide, lithiumbistrimethylsilylamide, etc.; and alkali metal carbonates such as sodiumcarbonate, potassium carbonate, etc., among which sodium hydride ispreferable.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 100° C.

The reaction time is about 30 minutes to 24 hours, preferably about 1hour to 12 hours.

Step A-2

This step is a hydrolysis reaction of esters, followed bydecarboxylation. A compound of the formula (15) can be prepared bystirring a compound of the formula (14) under heating in a solvent inthe presence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; alcohols such as methanol, ethanol, isopropyl alcohol, t-butanol,etc.; and water; and they can be used solely or in combination thereof.Preferred solvents in the present reaction are mixtures of an alcoholand water.

Examples of the bases used in the reaction include alkali metalcarbonates such as sodium carbonate, potassium carbonate, etc., andalkali metal hydroxides such as lithium hydroxide, sodium hydroxide,potassium hydroxide, etc., among which sodium hydroxide or potassiumhydroxide is preferred.

The reaction temperature is about 0° C. to 150° C., preferably about 60°C. to 120° C.

The reaction time is about 10 minutes to 12 hours, preferably about 30minutes to 6 hours.

In accordance with the Steps 1a-2, 1a-3 and 1a-4 of the Process 1a,compounds of the present invention can be prepared from a compound ofthe formula (15) obtained in the above Step A-2.

An example in the case where Alk¹ is a branched alkanediyl or alkenediylwill be illustrated below.

Step A-3

A compound of the formula (17) can be prepared by reacting a compound ofthe formula (14) with a compound of the formula (16) in a solvent in thepresence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;alcohols such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.;and polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,etc., and they can be used solely or in combination thereof. Preferredsolvents in the present reaction are N,N-dimethylformamide, etc.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; alkali metal alkoxidessuch as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.;alkali metal carbonates such as sodium carbonate, potassium carbonate,sodium bicarbonate, potassium bicarbonate, etc.; alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.;alkali metal carboxylates such as sodium acetate, potassium acetate,etc.; and alkali metal phosphates such as sodium phosphate, potassiumphosphate, etc., among which sodium hydride is preferred.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 100° C.

The reaction time is about 10 minutes to 24 hours, preferably about 30minutes to 12 hours.

Step A-4

In a similar manner to Step A-2, a compound of the formula (18) can beprepared from a compound of the formula (17).

In accordance with the Steps 1a-2, 1a-3 and 1a-4 of the Process 1a, thecompounds of the present invention can be prepared from a compound ofthe formula (18) obtained in the above Step A-4.

Process B

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R³ and R⁴ each has the same meaning as defined above, and 1″ is2 or 3).

In the above reaction scheme, R³ and R⁴ each has the same meaning asdefined above, Me is methyl, and Bn is benzyl.

Step B-1

A compound of the formula (20) can be prepared by reacting a compound ofthe formula (19) with a brominating agent in a solvent in the presenceof a radical initiator (for example, 2,2′-azobisisobutyronitrile orbenzoyl peroxide).

The solvent used in the reaction includes, for example, hydrocarbonssuch as benzene, etc., and halogenated hydrocarbons such as methylenechloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.,and they can be used solely or in combination thereof. Preferredsolvents in the present reaction are methylene chloride or carbontetrachloride.

The brominating agent used in the reaction includes, for example,bromine, N-bromosuccinimide, etc., among which N-bromosuccinimide ispreferred.

The reaction temperature is about room temperature to 120° C.,preferably about 60° C. to 100° C. The reaction time is about 10 minutesto 8 hours, preferably about 30 minutes to 4 hours.

Step B-2

In a similar manner to Step A-1 of Process A, a compound of the formula(22) can be prepared by reacting a compound of the formula (20) with acompound of the formula (21).

Step B-2′

In a similar manner to Step A-1 of Process A, a compound of the formula(22′) can be prepared by reacting a compound of the formula (20′)(prepared from a compound of the formula (15) and a compound of theformula (22) via several steps) with a compound of the formula (21).

Step B-3

A compound of the formula (23) can be prepared by hydrogenating acompound of the formula (22) for debenzylation in a solvent, followed bydecarboxylation.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; alcohols such as methanol, ethanol, isopropyl alcohol, t-butanol,etc.; and water; and they can be used solely or in combination thereof.Preferred solvents in the present reaction are alcohols.

Examples of the catalyst used for the debenzylation include palladiumcarbon, palladium hydroxide, Raney-Ni, platinum oxide, etc., among whichpalladium carbon is preferred.

The reaction temperature in the debenzylation is preferably about roomtemperature to 80° C., and the reaction temperature in thedecarboxylation is preferably 10° C. to 150° C.

The reaction time in the debenzylation is about 1 hour to 16 hours,preferably about 2 hours to 8 hours, and the reaction time in thedecarboxylation is about 5 minutes to 4 hours, preferably about 10minutes to 2 hours.

Step B-3′

In a similar manner to Step B-3 of Process B, a compound of the formula(23′) can be prepared from a compound of the formula (22′).

In accordance with the Steps 1-3, 1-4 and 1-5 of the process 1, thecompounds of the present invention can be prepared from a compound ofthe formula (23) or (23′) obtained in Step B-3 or B-3′.

Process C

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R⁴ has the same meaning as defined above, R³² is —CON(R¹)(R¹²)in which R¹¹ and R¹² each has the same meaning as defined above, and 1′is 1).

In the above reaction scheme, R⁴, R¹¹ and R¹² each has the same meaningas defined above, Me is methyl and t-Bu is tert-butyl.

Step C-1

An acid chloride can be prepared from a compound of the formula (24) ina similar manner to Step 1-1 of Process 1. The resulting acid chlorideis reacted with a compound of the formula (25) in a similar manner toStep 1-3 of Process 1 to give a compound of the formula (25).

Also, a compound of the formula (26) can be prepared by condensing acompound of the formula (24) with a compound of the formula (25) using acondensing agent (for example, WSC, HOBT). Alternatively, a compound ofthe formula (24) is converted into its mixed anhydride, followed byreaction with a compound of the formula (25) in the presence of a base,to give a compound of the formula (26).

Step C-2

In a similar manner to Step A-1 of Process A, a compound of the formula(28) can be prepared by reacting a compound of the formula (26) with acompound of the formula (27).

Step C-3

A compound of the formula (29) can be prepared by treating a compound ofthe formula (28) with an acid (trifluoroacetic acid, toluenesulfonicacid, methanesulfonic acid, etc.) in the presence or absence of asolvent under heating or at room temperature to convert the tert-butylester moiety into the carboxylic acid moiety, followed bydecarboxylation.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;alcohols such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and water; and they can be usedsolely or in combination thereof. Preferred solvents in the presentreaction are methylene chloride, chloroform or toluene.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 100° C. The reaction time is about 1 hour to 24hours, preferably about 2 hours to 12 hours.

Step C-4

In a similar manner to Step 1-2 of Process 1, a compound of the formula(30) can be prepared from a compound of the formula (29).

In accordance with the Steps 1-3, 1-4 and 1-5 of Process 1, thecompounds of the present invention can be prepared from a compound ofthe formula (30) obtained in the above Step C-4.

Process D

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R⁴ has the same meaning as defined above, R³³ is C₁₋₆ alkoxy orC₇₋₁₆ aralkyloxy, and 1′ is 1).

In the above reaction scheme, R⁴, X₂, Me and Et each has the samemeaning as defined above and R²⁶ is C₁₋₆ alkyl or C₇₋₁₆ aralkyl.

Step D-1

A compound of the formula (32) can be prepared by reacting a compound ofthe formula (31) with a compound of the formula (16) in a solvent in thepresence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; andpolar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc.; and they can be used solely or in combination thereof.A preferred solvents in the present reaction is N,N-dimethylformamide.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc., and alkali metalcarbonates such as sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, etc., among which sodium hydride ispreferred.

The reaction temperature is about 0° C. to 100° C., preferably aboutroom temperature to 80° C. The reaction time is about 2 hour to 48hours, preferably about 6 hours to 24 hours.

Step D-2

A compound of the formula (33) can be prepared by hydrolyzing the estermoiety of a compound of the formula (32) in a solvent in the presence ofa base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; alcohols such as methanol, ethanol, isopropyl alcohol, etc.; andwater, and they can be used solely or in combination thereof. Preferredsolvents in the present reaction are tetrahydrofuran or a mixture oftetrahydrofuran and ethanol or methanol.

Examples of the bases used in the reaction include alkali metalcarbonates such as sodium carbonate, potassium carbonate, etc.; aqueoussolutions of alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, etc., among which sodium hydroxide ispreferred.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 80° C.

The reaction time is about 1 hour to 24 hours, preferably about 2.5hours to 12 hours.

Step D-3

In a similar manner to Step 1-1 of Process 1, a compound of the formula(34) can be prepared from a compound of the formula (33).

Step D-4

This process is a conversion reaction from acid chlorides todiazoketones. A compound of the formula (35) can be prepared by reactinga compound of the formula (34) with diazomethane in a solvent in thepresence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc., and they can be used solely or in combination thereof. Preferredsolvents in the present reaction are diethyl ether or tetrahydrofuran.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which triethylamine is preferred.

The reaction temperature is about −20° C. to 50° C., preferably about 0°C. to room temperature.

The reaction time is about 2 hours to 48 hours, preferably about 6 hoursto 24 hours.

Step D-5

This process is one carbon homologation (Arndt-Eistert synthesis) byα-diazoketone rearrangement (Wolff rearrangement). A compound of theformula (35) is reacted by use of a silver catalyst (for example, silverbenzoate, silver oxide) in an alcohol in the presence of a base to givea compound of the formula (36).

The solvent (also served as the reaction reagents) used in the reactionincludes, for example, alcohols such as methanol, ethanol, isopropylalcohol, t-butanol, etc., and they can be used solely or in combinationthereof. Preferred solvents (also served as the reaction reagents) inthe present reaction are methanol or ethanol.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which triethylamine is preferred.

The reaction temperature is about room temperature to 120° C.,preferably about 60° C. to 120° C.

The reaction time is about 2 hours to 36 hours, preferably about 4 hoursto 18 hours.

Step D-6

In a similar manner to Step 1-2 of Process 1, a compound of the formula(37) can be prepared from a compound of the formula (36).

In accordance with the Steps 1-3, 1-4 and 1-5 of the above Process 1,the compounds of the present invention can be prepared from a compoundof the formula (37) obtained in the above Step D-6. The resultingcompound of the present invention is further subjected to the reactionsof Step 2-2 of Process 2, whereby the substituent —OR²⁶ can be convertedinto —OH.

Process E

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R⁴ has the same meaning as defined above, R³⁴ is —N(R¹³)(R¹⁴)in which R¹³ and R¹⁴ each has the same meaning as defined above), and 1′is 1).

In the above reaction scheme, R⁴, R¹³, R¹⁴, Me and t-Bu each has thesame meaning as defined above.

Step E-1

In a similar manner to Step A-1 of Process A, a compound of the formula(39) can be prepared by reacting a compound of the formula (38) with acompound of the formula (27).

Step E-2

In a similar manner to Step C-3 of Process C, a compound of the formula(40) can be prepared from a compound of the formula (39).

Step E-3

A compound of the formula (42) can be prepared by reacting a compound ofthe formula (40) with a compound of the formula (41) without or in asolvent and in the presence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohols such as methanol,ethanol, isopropyl alcohol, t-butanol, etc.; esters such as ethylacetate, methyl acetate, butyl acetate, etc.; and polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, etc.; and they can be usedsolely or in combination thereof. A preferred solvent in the presentreaction is tetrahydrofuran.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which triethylamine or a mixture of triethylamine anddimethylaminopyridine is preferred.

The reaction temperature is about 0° C. to 120° C., preferably aboutroom temperature to 100° C.

The reaction time is about 2 hours to 48 hours, preferably about 6 hoursto 24 hours.

Step E-4

In a similar manner to Step 1-2 of Process 1, a compound of the formula(43) can be prepared from a compound of the formula (42).

In accordance with the Steps 1-3,1-4 and 1-5 of the above Process 1, thecompounds of the present invention can be prepared from a compound ofthe formula (43) obtained in the above Step E-4.

Process F

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R⁴ has the same meaning as defined above and R³⁵ is —COO(R²⁵)in which R²⁵ is C₁-C₆ alkyl, and l′ is 1).

In the above reaction scheme, R⁴, R²⁵ and Bn each has the same meaningas defined above.

Step F-1

In a similar manner to Step 1-1 of Process 1, a compound of the formula(45) can be prepared from a compound of the formula (44).

Step F-2

A compound of the formula (47) can be prepared by reacting a compound ofthe formula (45) with a compound of the formula (46) in a solvent in thepresence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and esters such as ethylacetate, methyl acetate, butyl acetate, etc.; and they can be usedsolely or in combination thereof. A preferred solvent in the presentreaction is tetrahydrofuran.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which triethylamine is preferred.

The reaction temperature is about −30° C. to 80° C., preferably about−20° C. to room temperature.

The reaction time is about 2 hours to 48 hours, preferably about 6 hoursto 24 hours.

Step F-3

In a similar manner to Step A-1 of Process A, a compound of the formula(49) can be prepared by reacting a compound of the formula (47) with acompound of the formula (48).

Step F-4

A compound of the formula (49) was reacted in a similar manner to Step1-2 of Process 1, followed by debenzylation and decarboxylation to givea compound of the formula (50).

In accordance with the alternative process described in Step 1-3 andStep 1-5 of Process 1, the compounds of the present invention can beprepared from a compound of the formula (50) obtained in the above StepF-4.

Process G

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R³ and R⁴ each has the same meaning as defined above and l′ is1).

In the above reaction scheme, R³, R⁴ and Et each has the same meaning asdefined above.

Step G-1

In a similar manner to Step 1-1 of Process 1, a compound of the formula(52) can be prepared from a compound of the formula (51).

Step G-2

In a similar manner to Step D-4 of Process D, a compound of the formula(53) can be prepared from a compound of the formula (52).

Step G-3

In a similar manner to Step D-5 of Process D, a compound of the formula(54) can be prepared from a compound of the formula (53).

Step G-4

In a similar manner to Step D-6 of Process D, a compound of the formula(55) can be prepared from a compound of the formula (54).

In accordance with Steps 1-3, 1-4 and 1-5 of the above Process 1, thecompounds of the present invention can be prepared from a compound ofthe formula (55) obtained above in Step G-4.

Step G-5

In a similar manner to Step 1-4 of the above Process 1, a compound ofthe formula (55′) can be prepared from a compound of the formula (54).

In accordance with Steps 1a-2, 1a-3 and 1a-4 of the above Process 1a,the compounds of the present invention can be prepared from a compoundof the formula (55′) obtained in the above Step G-5.

Process H

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R³ and R⁴ each has the same meaning as defined above and 13 is0).

In the above reaction scheme, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R²³,Alk², ring A, ring B, ring C, m and n each has the same meaning asdefined above.

Step H-1

In a similar manner to Step 1-2 of Process 1, a compound of the formula(57) can be prepared from a compound of the formula (56).

Step H-2

In a similar manner to Step 1-3 of Process 1, a compound of the formula(58) can be prepared by reacting a compound of the formula (57) obtainedin Step of H-1 (or commercially available product) with a compound ofthe formula (3).

Step H-3

In a similar manner to Step 1-4 of Process 1, a compound of the formula(59) can be prepared from a compound of the formula (58).

Step H-4

In a similar manner to Step 1-5 of Process 1, a compound of the formula(1-3) which is one of the objective compounds can be prepared byreacting a compound of the formula (59) with a compound of the formula(8).

Process I

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R³ and R⁴ each has the same meaning as defined above and 14 is1 to 3).

In the above reaction scheme, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, 14, m,n, ring A, ring C, Bn, Me, Alk¹, Alk² and X₂ each has the same meaningas defined above.

Step I-1

In a similar manner to Step 1-3 of Process 1, a compound of the formula(61) can be prepared by reacting a compound of the formula (60) with acompound of the formula (3).

Step I-2

Under conditions similar to Step 1-2 of Process 1, with the proviso thatpalladium hydroxide is used as a catalyst, a compound of the formula(62) can be prepared from a compound of the formula (61).

Step I-3

A compound of the formula (64) can be prepared by reacting a compound ofthe formula (62) with a compound of the formula (63) in a solvent in thepresence of a base. Alternatively, X₂-(Alk¹)₁₄-COOEt (in the formula,X₂, Alk¹, 14 and Et each has the same meaning as defined above) may beused in place of a compound of the formula (63).

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;alcohols such as methanol, ethanol, isopropyl alcohol, t-butanol, etc.;esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; polarsolvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide,etc.; and they can be used solely or in combination thereof. A preferredsolvent in the present reaction is N,N-dimethylformamide.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; alkali metal alkoxidessuch as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.;alkali metal carbonates such as sodium carbonate, potassium carbonate,etc.; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, etc.; alkali metal carboxylates such assodium acetate, potassium acetate, etc.; and alkali metal phosphatessuch as sodium phosphate, potassium phosphate, etc., among whichpotassium carbonate or sodium hydride is preferred.

The reaction temperature is about 0° C. to 150° C., preferably aboutroom temperature to 100° C.

The reaction time is about 1 hour to 48 hours, preferably about 2 hoursto 24 hours.

Step I-4

In a similar manner to Step 1-4 of Process 1, a compound of the formula(65) can be prepared from a compound of the formula (64).

Step I-5

In a similar manner to Step 1-5 of Process 1, a compound of the formula(1-4) which is one of the objective compounds can be prepared byreacting a compound of the formula (65) with a compound of the formula(8).

Process J

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R³, R⁴ and Alk¹ each has the same meaning as defied above and14 is 1 to 3).

In the above reaction scheme, R³, R⁴, Me, Alk¹, 14 and X₂ each has thesame meaning as defined above.

Step J-1

In a similar manner to Step I-3 of Process I, a compound of the formula(67) can be prepared by reacting a compound of the formula (66) with acompound of the formula (63). Alternatively, X₂-(Alk¹)₁₄-COOEt (in theformula X₂, Alk¹, 14 and Et each has the same meaning as defined above)may be used in place of a compound of the formula (63).

Step J-2

In accordance with the Step I-4 of Process I, a compound of the formula(68) can be prepared from a compound of the formula (67).

In a similar manner to Steps 1a-2, 1a-3 and 1a-4 of Process 1a, thecompounds of the present invention can be prepared from a compound ofthe formula (68) obtained in the above Step J-2.

Process K

The following is an example of the process for preparing a compound ofthe formula (1) wherein ring B is

(wherein R³, R⁴, 14 and Alk¹ each has the same meaning as definedabove).

In the above reaction scheme, R³, R⁴, Me, 14, Alk¹ and X₂ each has thesame meaning as defined above.

Step K-1

In a similar manner to Step I-3 of Process I, a compound of the formula(70) can be prepared by reacting a compound of the formula (69) with acompound of the formula (63). Alternatively, X₂-(Alk¹)₁₄-COOEt (in theformula X₂, Alk¹, 14 and Et each has the same meaning as defined above)may be used in place of a compound of the formula (63).

Step K-2

In a similar manner to Step I-4 of Process I, a compound of the formula(71) can be prepared from a compound of the formula (70).

In accordance with the Steps 1a-2, 1a-3 and 1a-4 of the above Process1a, the compounds of the present invention can be prepared from acompound of the formula (71) obtained in the above Step K-2.

Process L

The following is an example of the process for preparing a compound ofthe formula (1) wherein R³ of the ring B, and R¹⁰ of the X are takentogether to form

(wherein R⁴, 14 and Alk¹ each has the same meaning as defined above).

In the above reaction scheme, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, 14, m,ring A, ring C, Alk¹ and Alk² each has the same meaning as definedabove.

Step L-1

A compound of the formula (1-5) obtained by debenzylation of a compound(wherein R²⁶ is benzyl) obtained in the Process 1 and the Process D isreacted with a phosgene equivalent reagent (for example, triphosgene ordiphosgene, etc.) in a solvent in the presence of a base to give acompound of the formula (1-6).

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and they can be used solely orin combination thereof. A preferred solvent in the present reaction ischloroform.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which triethylamine is preferred.

The reaction temperature is about −20° C. to 100° C., preferably about0° C. to room temperature.

The reaction time is about 10 minutes to 4 hours, preferably about 30minutes to 2 hours.

Process M

The following is an example of the process for preparing a compound ofthe formula (1) wherein R¹⁰ is other than hydrogen.

In the above reaction scheme, R¹, R², R³, R⁴, R²³, l, n, X₂, ring A,ring B, and Alk¹ each has the same meaning as defined above, and R^(10′)is C₁-C₆ alkyl or C₃-C₇ cycloalkyl).

Step M-1

A compound of the formula (73) can be prepared by reacting a compound ofthe formula (6) obtained in the Step 1-3 of Process 1 with a compound ofthe formula (72) in a solvent in the presence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; andpolar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc.; and they can be used solely or in combination thereof.A preferred solvent in the present reaction is N,N-dimethylformamide.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; alkali metal alkoxidessuch as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.;alkali metal carbonates such as sodium carbonate, potassium carbonate,etc.; alkali metal carboxylates such as sodium acetate, potassiumacetate, etc.; and alkali metal phosphates such as sodium phosphate,potassium phosphate, etc., among which sodium hydride is preferred.

The reaction temperature is about 0° C. to 100° C., preferably aboutroom temperature to 80° C.

The reaction time is about 1 hour to 24 hours, preferably about 2 hoursto 8 hours.

In accordance with the above Steps 1-4 and 1-5, the compounds of thepresent invention can be prepared from a compound of the formula (73)obtained in the above Step M-1.

Process N

The following is an example of the process for preparing a compound ofthe formula (1) wherein R⁸ and R⁹ are each —CONH(R^(19′)) (whereinR^(19′) is C₁-C₆ alkyl).

In the above reaction scheme, R⁵, R⁶, R⁷, R²⁵ and ring C each has thesame meaning as defined above.

Step N-1

A compound of the formula (75) can be prepared by reacting a compound ofthe formula (74) with thionyl chloride or oxalyl chloride in a solvent.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and esters such as ethylacetate, methyl acetate, butyl acetate, etc.; and they can be usedsolely or in combination thereof. A preferred solvent used in thepresent reaction is toluene containing a catalytic amount ofN,N-dimethylformamide.

The reaction temperature is about room temperature to 120° C.,preferably about 50° C. to 100° C.

The reaction time is about 10 minutes to 6 hours, preferably about 30minutes to 3 hours.

Step N-2

A compound of the formula (77) can be prepared by reacting a compound ofthe formula (75) with a compound of the formula (76) in a solvent in thepresence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; and esters such as ethylacetate, methyl acetate, butyl acetate, etc.; and they can be usedsolely or in combination thereof. Preferred solvents in the presentreaction are methylene chloride or tetrahydrofuran.

Examples of the bases used in the reaction include organic bases such astriethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine,etc., among which triethylamine is preferred.

The reaction temperature is about −40° C. to 60° C., preferably about−30° C. to room temperature.

The reaction time is about 2 hours to 48 hours, preferably about 6 hoursto 24 hours.

Step N-3

A compound of the formula (78) can be prepared by reacting a compound ofthe formula (77) with paraformaldehyde or formalin without or in asolvent in the presence of a catalytic amount of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohols such as methanol,ethanol, isopropyl alcohol, t-butanol, etc.; esters such as ethylacetate, methyl acetate, butyl acetate, etc.; and polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, etc.; and they can be usedsolely or in combination thereof. A preferred solvent in the presentreaction is tetrahydrofuran.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; alkali metal alkoxidessuch as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.;alkali metal hydroxides such as sodium hydroxide, potassium hydroxide,lithium hydroxide, etc.; alkali metal carbonates such as sodiumcarbonate, potassium carbonate, etc.; and organic bases such astriethylamine, diethylamine, pyridine, etc., among which potassiumt-butoxide, sodium ethoxide or potassium hydroxide is preferred.

The reaction temperature is about 0° C. to 100° C., preferably aboutroom temperature to 80° C.

The reaction time is about 10 minutes to 24 hours, preferably about 30minutes to 12 hours.

In accordance with the above Processes 1, 1a and 2, the compounds of thepresent invention can be prepared using a compound of the formula (78)obtained in the above Step N-3 in place of a compound of the formula(8).

Process O

The following is an example of the process for preparing a compound ofthe formula (1) wherein R⁸ and R⁹ are each —COOR²⁵ (wherein R²⁵ is C₁-C₆alkyl).

In the above reaction scheme, R⁵, R⁶, R⁷, R²⁵ and ring C each has thesame meaning as defined above.

Step O-1

In a similar manner to Step N-3 of Process N, a compound of the formula(80) can be prepared from a compound of the formula (79).

In accordance with the above Processes 1, 1a and 2, the compounds of thepresent invention can be prepared using a compound of the formula (80)obtained in the above Step O-1 in place of a compound of the formula(8).

Process P

The following is an example of the process for preparing a compound ofthe formula (1) wherein m is 2 or 3. In this process,tert-butyldimethylsilyl (TBS) may be used in place of benzyl (Bn).

In the above reaction scheme, R⁵, R⁶, R⁷, R⁸, R⁹, X₂, m, Bn and ring Ceach has the same meaning as defined above.

Step P-1

A compound of the formula (83) can be prepared by reacting a compound ofthe formula (81) with a compound of the formula (82) in a solvent in thepresence of a base.

The solvent used in the reaction includes, for example, ethers such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme,etc.; hydrocarbons such as benzene, toluene, hexane, xylene, etc.;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, etc.; alcohols such as methanol,ethanol, isopropyl alcohol, t-butanol, etc.; esters such as ethylacetate, methyl acetate, butyl acetate, etc.; and polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, etc.; and they can be usedsolely or in combination thereof. Preferred solvents in the presentreaction are N,N-dimethylformamide or tetrahydrofuran.

Examples of the bases used in the reaction include alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; alkali metal alkoxidessuch as sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.;alkali metal carbonates such as sodium carbonate, potassium carbonate,etc.; and organoalkali metals such as lithium diisopropylamide, etc.,among which sodium hydride or lithium diisopropylamide is preferred.

The reaction temperature is about 0° C. to 100° C., preferably aboutroom temperature to 80° C.

The reaction time is about 30 minutes to 48 hours, preferably about 2hours to 24 hours.

Step P-2

In a similar manner to Step 2-2 of Process 2, a compound of the formula(84) can be prepared from a compound of the formula (83).

In accordance with the above Processes 1, 1a and 2, the compounds of thepresent invention can be prepared using a compound of the formula (84)obtained in the above Step P-2 in place of a compound of the formula(8).

EXAMPLES

The present invention is illustrated in more detail by Examples givenbelow, but it goes without saying that the present invention is notlimited thereto. In the Examples, Me is methyl, Et is ethyl, tBu ist-butyl and TBS is tert-butylmethylsilyl.

Example 1 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]phenyl-aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester a) Phenylmalonic AcidDichloride

Thionyl chloride (13.7 mL) was added dropwise to a mixture ofphenylmalonic acid (11.31 g), dimethylformamide (230 μL) and toluene (27mL) under ice-cooling. The mixture was stirred at 80° C. for 70 minutes,and the solvent was removed off by evaporation. After azeotropicdistillation with toluene, the residue was dried in vacuo to give thetitle compound (11.61 g).

b) Phenylmalonic Acid Diethylamide

To a mixed solution of ethylamine in tetrahydrofuran (2M, 45.5 mL),triethylamine (13.9 mL) and methylene chloride (80 mL) was dropwiseadded the phenylmalonic acid dichloride (8.99 g) obtained in Example1-a) at −20° C. The mixture was stirred overnight while the temperaturewas raised to room temperature, and then diluted with ethyl acetateafter addition of 3N hydrochloric acid. The organic layer was washedwith saturated brine, saturated aqueous sodium bicarbonate and saturatedbrine, dried over sodium sulfate and concentrated. The resulting solidwas washed with ethyl acetate and hexane to give the title compound(4.85 g) as a white powder.

c) 2-Hydroxymethyl-2-phenylmalonic acid diethylamide

The phenylmalonic acid diethylamide (2.34 g) obtained in Example 1-b)and paraformamide (390 mg) were suspended in tetrahydrofuran (20 ml),and to this suspension was added potassium hydroxide (catalytic amount)at 60° C. The mixture was stirred for 5 hours and concentrated to removethe solvent. The residue was chromatographed on a column of silica gelwith ethyl acetate:hexane=1:1 to give the title compound (2.31 g).

d) 4′-Trifluoromethylbiphenyl-2-carboxylic acid chloride

To a mixture of 4′-trifluoromethylbiphenyl-2-carboxylic acid (5.06 g),dimethylformamide (catalytic amount) and methylene chloride (30 mL) wasadded dropwise oxalyl chloride (2.43 mL) under ice-cooling. The mixturewas stirred at room temperature for 100 minutes and the solvent wasremoved by evaporation. After azeotropic distillation with toluene, theresidue was dried in vacuo to give the title compound (5.40 g).

e) 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]phenyl-acetic acidethyl ester

To a mixture of 4-aminophenylacetic acid ethyl ester (3.41 g),triethylamine (3.2 mL) and methylene chloride (30 mL) was added dropwisea solution of the 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride(5.40 g) obtained in Example 1-d) in methylene chloride (10 mL) underice-cooling, and the mixture was stirred at room temperature overnight.After addition of 1N hydrochloric acid, the reaction mixture was dilutedwith ethyl acetate, and the organic layer was washed with saturatedbrine, saturated aqueous sodium bicarbonate and saturated brine, driedover sodium sulfate, and then concentrated to give the title compound(8.12 g).

f) 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]phenyl-acetic acid

The 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acidethyl ester (8.12 g) obtained in Example 1-e) was dissolved in 40 mL oftetrahydrofuran and 20 mL of ethanol. After addition of 4N sodiumhydroxide (5 mL), the solution was stirred at room temperature for 5hours and concentrated. The powder formed upon addition of 1Nhydrochloric acid was collected by filtration and dried in vacuo to givethe title compound (7.48 g).

g) 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]phenyl-acetic acid2,2-bisethylcarbamoyl-2-phenylethyl ester

The 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acid(519 mg) obtained in Example 1-f), the 2-hydroxymethyl-2-phenylmalonicaid diethylamide (317 mg) obtained in Example 1-c),dimethylaminopyridine (171 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(WSC.HCl)(268 mg) were dissolved in methylene chloride (5 ml). Thesolution was stirred at room temperature for 6 hours and the solvent wasremoved off by evaporation. The residue was purified by columnchromatography on silica gel with ethyl acetate:hexane=1:1 to 3:2 togive the title compound (725 mg) (see Table 1).

Example 1-22-Phenyl-2-{2-[4-(4′-trifluoromethylbiphenyl-2-carbonyloxy)phenyl]acetoxymethyl}malonicacid diethyl ester a) 2-Hydroxymethyl-2-phenylmalonic acid diethyl ester

Paraformaldehyde (720 mg) was suspended in phenylmalonic acid diethylester (4.73 g), and a catalytic amount of potassium hydroxide was addedthereto at 60° C. After stirring for 1.5 hours, the reaction mixture waspurified by column chromatography on silica gel with ethylacetate:hexane=1:5 to 1:2 to give the title compound (4.96 g).

b) 2-[2-(4-(Benzyloxyphenyl)acetoxymethyl]-2-phenylmalonic acid diethylester

4-Benzyloxyphenylacetic acid (1.09 g) was suspended in methylenechloride (50 mL) and the suspension was dissolved by addition ofdimethylaminopyridine (0.511 g). To the solution was added the2-hydroxymethyl-2-phenylmalonic acid diethyl ester (1.20 g) obtained inExample 1-2a), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (0.864 g) was portionwise added thereto. The mixture wasstirred at room temperature overnight and then concentrated. The residuewas purified by column chromatography on silica gel with ethylacetate:hexane=1:4 to give the title compound (1.95 g) as a colorlessoil.

c) 2-[2-(4-(Hydroxyphenyl)acetoxymethyl]-2-phenylmalonic acid diethylester

The 2-[2-(4-(Benzyloxyphenyl)acetoxymethyl]-2-phenyl-malonic aciddiethyl ester (1.95 g) obtained in Example 1-2b) was dissolved inmethanol (2.5 mL). The solution was subjected to hydrogenation in thepresence of 7.5% palladium-carbon (0.200 g) under normal pressure for 4hours. The reaction solution was filtered through a Celite pad andconcentrated to give the title compound (1.71 g) as a colorless oil.

d)2-Phenyl-2-{2-[4-(4′-trifluoromethylbiphenyl-2-carbonyloxy)phenyl]acetoxymethyl}malonicacid diethyl ester

4′-Trifluoromethylbiphenyl-2-carboxylic acid (0.266 g) was suspended inmethylene chloride (10 mL), and the suspension was dissolved by additionof 4-dimethylaminopyridine (0.122 g). To the solution was added the2-[2-(4-(hydroxyphenyl)acetoxymethyl]-2-phenylmalonic acid diethyl ester(0.400 g) obtained in Example 1-2c), and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.192 g)was portionwise added thereto. The mixture was stirred at roomtemperature overnight and then concentrated. The residue was purified bycolumn chromatography on silica gel with ethyl acetate:hexane=1:3 togive the title compound (0.55 g) as an amorphous powder (see Table 1).

Example 1-32-(2-{3-Methyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester a) 2-(3-Methyl-4-nitrophenyl)malonic acid diethylester

Sodium hydride (60% mineral oil; 0.599 g) was suspended indimethylformamide (10 mL), and a solution of malonic acid diethyl ester(2.00 g) in dimethylformamide (10 mL) was added dropwise thereto underice-cooling. After foam generation is stopped, a solution of4-fluoro-2-methylnitrobenzene (1.94 g) in dimethylformamide (5 mL) wasadded thereto, and the reaction temperature was raised to 100° C.,followed by stirring for 6 hours. The reaction mixture was concentrated,acidified with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed successively with water and saturated brine,dried over sodium sulfate and concentrated. The residue was purified bycolumn chromatography on silica gel with ethyl acetate:hexane=1:5 togive the title compound (1.65 g) as a yellow oil.

b) (3-Methyl-4-nitrophenyl)acetic acid

Potassium hydroxide (0.168 g) was dissolved in 7 mL of methanol and 1 mLof water, and the 2-(3-methyl-4-nitrophenyl)malonic acid diethyl ester(0.250 g) obtained in Example 1-3a) was dissolved in the solution. Thesolution was stirred at 100° C. for 2 hours and concentrated. Theresidue was acidified with 2N hydrochloric acid and extracted with ethylacetate. The extract was washed with saturated brine, dried over sodiumsulfate and concentrated to give the title compound (0.143 g) as ayellow solid.

c) 2-[2-(3-Methyl-4-nitrophenyl)acetoxymethyl]-2-phenyl-malonic aciddiethyl ester

The (3-Methyl-4-nitrophenyl)acetic acid (0.143 g) obtained in Example1-3b) was dissolved in methylene chloride (5 mL). To the solution wereadded 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (0.195 g)obtained in Example 1-2a), 4-dimethylaminopyridine (0.090 g) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.141 g),and the mixture was stirred at room temperature overnight. The reactionmixture was concentrated and the residue was purified by columnchromatography on silica gel with ethyl acetate:hexane=1:4 to give thetitle compound (0.219 g) as a yellow oil.

d) 2-[2-(4-Amino-3-methylphenyl)acetoxymethyl]-2-phenyl-malonic aciddiethyl ester

The 2-[2-(3-Methyl-4-nitrophenyl)acetoxymethyl]-2-phenyl-malonic aciddiethyl ester (0.219 g) obtained in Example 1-3c) was dissolved inmethanol (3 mL). The solution was subjected to hydrogenation in thepresence of 7.5% palladium-carbon (0.030 g) under normal pressure togive the title compound (0.197 g) as a yellow oil.

e)2-(2-{3-Methyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester

In a similar manner to Example 1d),4′-trifluoro-methyl-2-biphenylcarboxylic acid (0.124 g) was convertedinto its corresponding acid chloride. On the other hand, the titlecompound (0.215 g) was obtained as a colorless amorphous from the2-[2-(4-amino-3-methylphenyl)acetoxymethyl]-2-phenylmalonic acid diethylester (0.197 g) obtained in Example 1-3d) in a similar manner to Example1e)(see Table 1).

Example 1-42-(2-{4-[Methyl-(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester a){4-[Methyl-(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid ethyl ester

Sodium hydride (51 mg) was dissolved in dimethylformamide (5 mL), andthe solution was cooled to 0° C. To the solution was added the4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylacetic acid ethylester (500 mg) obtained in Example 1e), and the mixture was stirred forone hour. After addition of iodomethane (183 mg), the mixture wasstirred at room temperature for 3 hours and water was then added. Thereaction solution was concentrated, diluted with ethyl acetate, andwashed with water. The resulting solution was dried over sodium sulfateand purified by column chromatography on silica gel with hexane:ethylacetate=4:1 to give the title compound (141 mg).

b)2-(2-{4-[Methyl-(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester

The{4-[Methyl-(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid ethyl ester (141 mg) obtained in Example 1-4a) was subjected toreactions similar to those in Examples 1f) and 1g) to give the titlecompound (56 mg)(see Table 1).

Example 1-5{3-Ethyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester a)3-Ethyl-4-nitrophenylacetic acid ethyl ester

To a solution of 4-nitrophenylacetic acid ethyl ester (1.63 g) intetrahydrofuran (100 mL) was dropwise added 2M ethyl magnesium chloridein tetrahydrofuran (3 mL) at −15° C. under argon atmosphere, and themixture was stirred at the same temperature for 30 minutes. Afterfurther dropwise addition of 2M ethyl magnesium chloride intetrahydrofuran (3 mL), the mixture was stirred at −15° C. for one hour,and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.0 g) was added theretoat the same temperature. The mixture was stirred overnight, and water(300 mL) was added thereto, followed by extraction with chloroform (150mL×3). The organic layers were combined, washed with saturated brine,dried over sodium sulfate and purified by column chromatography onsilica gel with hexane:ethyl acetate=10:1 to give the title compound(1.09 g).

b){3-Ethyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester

The 3-ethyl-4-nitrophenylacetic acid ethyl ester (1.05 g) obtained inExample 1-5a) was subjected to reactions similar to those in Example1-3d), Example 1e), Example 1f) and Example 1g) to give the titlecompound (1.60 g)(see Table 1).

Examples 1-6 to 1-83

Compounds of Examples 1-6 to 1-85 were obtained in a similar manner toExamples 1 to 1-5. The compounds obtained were shown in Tables 2 to 17.

TABLE 1 Example Structure NMR (δ, 300 MHz, CDCl₃) 1

1.05(6H, t, J=7.3Hz), 3.18-3.29(4H, m), 3.53(2H, s), 4.83(2H, s),6.95(1H, br-s), 7.02-7.23(8H, m), 7.27-7.36(3H, m), 7.41-7.47(1H, m),7.49-7.63(4H, m), 7.65-7.72(2H, m), 7.77-7.84(1H, m) 1-2

1.19(6H, t, J=9.2Hz), 3.53(2H, s), 4.18(4H, q, J=9.2Hz), 4.82(2H, s),6.79(2H, d, J=12Hz), 7.14(2H, d, J=12Hz), 7.29(5H, brs), 7.38-7.73(7H,m), 8.09(1H, dd, J=1.2Hz, J=7.5Hz). 1-3

1.21(6H, t, J=7.1Hz), 1.67(3H, s), 3.47(2H, s), 4.20(4H, q, J=7.1Hz),4.82(2H, s), 6.89((1H, brs), 6.92(1H, brs), 7.00(1H, d, J=10.6Hz),7.30(5H, brs), 7.42-7.84(9H, m). 1-4

1.22(6H, t, J=7.2Hz) 3.23 (3H, s), 3.40(2H, s), 4.21(4H, q, J=7.2Hz),4.83(2H, s), 6.10(2H, d, J=8.3Hz), 6.70(2H, d, J=8.3Hz), 7.07-7.61(13H,m) 1-5

0.93(3H, t, J=7.5Hz), 1.05(6H, t, J=7.3Hz), 1.94(2H, q, J=7.5Hz),3.13-3.28(4H, m), 3.53(2H, s), 4.83(2H, s), 6.80-7.84(19H, m)

TABLE 2 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-6 

3.56(2H, s), 3.65-3.78(2H, s), 4.55(2H, s), 5.49(1H, br), 7.01(1H, brs),7.05-7.83(20H, m). 1-7 

1.39(3H, d, J=7.2 Hz), 3.48-3.68(2H, m), 3.70-3.89(2H, m), 4.44 (1H, d,J=10.6Hz), 4.66 (1H, d, J=10.6Hz), 5.46 (1H, br), 6.96((1H, brs),7.02-7.84(20H, m). 1-8 

3.50(2H, s), 3.68-4.00 (3H, m), 4.42(1H, dd, J=6.0, 11.0 Hz), 4.62(1H,dd, J=7.9, 11.0Hz), 5.68 (1H, t, J=6.8 Hz), 6.95(1H, s), 7.03- 7.17(4H,m), 7.17- 7.36(5H, m), 7.44(1H, dd, J=1.5, 7.6Hz), 7.48-7.64(4H, m),7.65-7.71(2H, m), 7.80 (1H, dd, J=1.5, 7.6 Hz) 1-9 

1.20(6H, t, J=7.2 Hz), 3.51(2H, s), 4.20(4H, q, J=7.2 Hz), 4.81(2H, s),6.92(1H, br-s), 7.04-7.18(4H, m), 7.24-7.35(5H, m), 7.44(1H, dd, J=1.5,7.1 Hz), 7.48-7.64(4H, m), 7.65-7.73(2H, m), 7.81(1H, dd, J=1.5, 7.1Hz)1-10

1.47-1.76(6H, m), 1.90-2.03(2H, m), 3.60(2H, s), 3.71- 3.85(2H, m),4.10(2H, s), 6.94(1H, br-s), 7.12-7.20(4H, m), 7.44(1H, dd, J=1.2, 7.4Hz), 7.49-7.64(4H, m), 7.65-7.72(2H, m), 7.80(1H, dd, J=1.2, 7.4 Hz)

TABLE 3 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-11

1.18(6H, d, J=6.4 Hz), 1.20(6H, d, J=6.0 Hz), 3.50(2H, s), 4.80(2H, s),5.08(1H, sept, J=6.4 Hz), 5.08(1H, sept, J=6.0 Hz), 6.92(1H, s),7.05-7.16(4H, m), 7.27-7.32(5H, m), 7.41-7.47(1H, m), 7.49-7.63(4H, m),7.65-7.72(2H, m), 7.80 (1H, dd, J=1.5, 7.1 Hz) 1-12

3.53(2H, s), 3.74-3.97(4H, m), 4.87(2H, s), 6.94(1H, s), 7.00-7.07(2H,m), 7.09-7.20(4H, m), 7.31-7.47(6H, m), 7.49-7.64(4H, m), 7.65-7.72(2H,m), 7.80 (1H, dd, J=1.5, 7.5 Hz) 1-13

3.51(2H, s), 3.71(6H, s), 4.81(2H, s), 6.92(1H, br-s), 7.05-7.16(4H, m),7.22-7.35(5H, m), 7.41-7.46(1H, m), 7.49-7.63(4H, m), 7.65-7.71(2H, m),7.81 (1H, dd, J=1.5, 7.2 Hz) 1-14

1.20(6H, t, J=7.1 Hz), 1.29-1.81(10H, br), 2.40(2.53(1H, m), 3.52(2H,s), 4.13(4H, q, J=7.1 Hz), 4.48(2H, s), 6,93(1H, brs), 7.14(4H, brs),7.39-7.83(8H, m). 1-15

1.27-1.44(5H, m), 1.46-1.61(3H, m), 1.79-1.90(2H, m), 3.57 (2H, s),3.72-3.87(2H, m), 4.07(2H, s), 5.71-5.81(1H, m), 6.94(1H, br-s),7.10-7.21(4H, m), 7.40-7.47(1H, m), 7.49-7.63(4H, m), 7.65-7.72(2H, m),7.77-7.83(1H, m)

TABLE 4 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-16

1.22(6H, t, J=7.2 Hz), 3.57(2H, s), 4.21(4H, q, J=7.2 Hz), 4.83(2H, s),7.20(1H, d, J=8.5 Hz), 7.28-7.67(12H, m), 7.76(1H, d, J=7.4) 1-17

1.20(6H, t, J=7.1 Hz), 3.53(2H, s), 4.19(4H, q, J=7.1Hz), 4.82(2H, s),6.91(1H, d, J=8.3 Hz), 7.11-7.56(16H, m), 8.33(1H, dd, J=7.8, 1.8 Hz),9.62(1H, br.s) 1-18

1.05(3H, m), 1.22(6H, t, J=7.2 Hz), 1.58(2H, m), 1.99(2H, m), 3.57(2H,s), 4.21(6H, m), 4.85(2H, s), 7.04-7.60(12H, m), 8.30(1H, m), 10.07(1H,br.s) 1-19

1.22(6H, t, J=6.9 Hz), 3.60(2H, s), 4.20(4H, q, J=6.9 Hz), 4.85(2H, s),7.12-7.37(9H, m), 7.63-7.73(2H, m), 7.79-7.86(1H, m), 7.90-8.00(1H, m).1-20

1.18(6H, t, J=6.8 Hz), 3.51(2H, s), 4.17(4H, q, J=6.8 Hz), 4.80(2H, s),6.70(2H, d, J=12 Hz), 7.09(2H, d, J=12 Hz), 7.27(5H, brs), 7.41-7.83(8H,m), 8.21(1H, d, J=10 Hz).

TABLE 5 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-21

1.18(6H, t, J=7.2 Hz), 3.49(2H, s), 4.15(4H, q, J=7.2 Hz), 4.80(2H, s),7.07(1H, d, J=8.6 Hz), 7.27-7.54(17H, m), 7.88(1H, d, J=6.2 Hz) 1-22

1.16-1.83(20H, m), 3.50(2H, s), 4.80-4.91(2H, m), 4.82(2H, s), 6.93(1H,br-s), 7.05-7.17(4H, m), 7.27-7.34(5H, m), 7.41-7.47(1H, m),7.49-7.63(4H, m), 7.65-7.72(2H, m), 7.80 (1H, dd, J=1.5, 7.2 Hz) 1-23

0.95-1.22(6H, m), 1.23-1.43(4H, m), 1.50-1.71(6H, m), 1.71-1.90(4H, m),3.52 (2H, s), 3.69-3.83(2H, m), 4.84(2H, s), 6.95(1H, br-s),7.04-7.35(11H, m), 7.41-7.48(1H, m), 7.49-7.65(4H, m), 7.66-7.73(2H, m),7.77-7.84(1H, m) 1-24

3.58(2H, s), 5.06(2H, s), 6.81(1H, br-s), 6.99-7.05(4H, m),7.08-7.16(2H, m), 7.24-7.47(14H, m), 7.50-7.67(6H, m), 7.80 (1H, dd,J=1.5, 7.5 Hz), 9.08(2H, br-s) 1-25

1.04(6H, d, J=6.4 Hz), 1.09(6H, d, J=6.8 Hz), 3.52(2H, s), 3.95-4.09(2H,m), 4.83(2H, s), 6.92-7.03(3H, m), 7.03-7.10(2H, m), 7.11-7.23(4H, m),7.27-7.36(3H, m), 7.41-7.47(1H, m), 7.49-7.64(4H, m), 7.65-7.72(2H, m),7.80 (1H, dd, J=1.5, 7.5 Hz)

TABLE 6 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-26

1.19(6H, t, J=7.1 Hz), 3.24(2H, s), 3.59(2H, s), 4.15(4H, q, J=7.1 Hz),4.32(2H, s), 6.80-6.88(2H, m), 6.93(1H, brs), 7.11-7.28(7H, m),7.39-7.83(8H, m) 1-27

1.21(6H, t, J=7.1 Hz), 2.14(3H, s), 3.51(2H, s), 4.19(4H, q, J=7.1 Hz),4.80(2H, s), 6.87(1H, brs), 6.91-7.02(3H, m), 7.19-7.34(5H, m),7.40-7.85(8H, m). 1-28

3.56(2H, s), 3.71-3.95 (4H, m), 4.87(2H, s), 6.75-6.83(2H, m),7.05-7.19(4H, m), 7.29-7.44(6H, m), 7.47-7.60(3H, m), 7.62-7.73(3H, m),8.05-8.12(1H, m) 1-29

3.55(2H, s), 3.70-3.94 (4H, m), 4.86(2H, s), 6.71-6.79(2H, m),7.01-7.09(2H, m), 7.11-7.18(2H, m), 7.27-7.54(12H, m), 7.57-7.66(1H, m),7.94-8.01(1H, m) 1-30

0.95(3H, t, J=7.4 Hz), 1.45-1.60(2H, m), 1.76-1.88(2H, m), 3.62 (2H, s),3.79-3.97(4H, m), 4.08(2H, t, J=6.4 Hz), 4.90(2H, s), 6.99-7.06(2H, m),7.10-7.21(6H, m), 7.31-7.41(5H, m), 7.48-7.56(1H, m), 7.96 (1H, dd,J=1.8, 8.0 Hz)

TABLE 7 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-31

0.97-1.10(6H, m), 1.12 (6H, t, J=6.8 Hz), 1.54- 1.78(4H, m), 2.05-2.17(1H, m), 3.54(2H, s), 4.13 (4H, q, J=6.8 Hz), 4.50 (2H, s), 6.93(1H,brs), 7.14(4H, brs), 7.40-7.82(8H, m). 1-32

3.51(2H, s), 3.85(4H, m), 4.86(2H, s), 6.88(1H, s), 7.00-7.54(19H, m),7.89(1H, m) 1-33

3.56(2H, s), 3.84(4H, m), 4.86(2H, s), 6.91(1H, d, J=8.3 Hz),7.07-7.55(18H, m), 8.32(1H, dd, J=7.9, 1.9Hz), 9.64(1H, s) 1-34

1.23(6H, t, J=7.1 Hz), 3.70(2H, s), 4.22(4H, t, J=7.1 Hz), 4.81(2H, s),7.02(1H, brs), 7.13-7.97(16H, m). 1-35

0.85(6H, t, J=7.5 Hz), 1.37-1.51(4H, m), 3.13-3.22(4H, m), 3.53(2H, s),4.84(2H, s), 6.96(1H, br-s), 7.02-7.09(2H, m), 7.10-7.24(6H, m),7.27-7.35(3H, m), 7.41-7.47(1H, m), 7.49-7.63(4H, m), 7.65-7.72(2H, m),7.80(1H, dd, J=1.6, 8.0 Hz)

TABLE 8 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-36

2.73(6H, d, J=4.9 Hz), 3.53 (2H, s), 4.81(2H, s), 6.94 (1H, br-s),7.01-7.09(4H, m), 7.11-7.21(4H, m), 7.27-7.35(3H, m), 7.41-7.47(1H, m),7.49-7.63(4H, m), 7.66-7.72(2H, m), 7.81 (1H, dd, J=1.5, 7.5 Hz) 1-37

1.20(6H, t, J=7.0 Hz), 3.50 (2H, s), 4.21(4H, q, J=7.0 Hz), 4.90(2H, s),6.93(1H, br-s), 7.04-7.15(4H, m), 7.15-7.21(1H, m), 7.38-7.47(2H, m),7.49-7.64(5H, m), 7.66-7.72(2H, m), 7.81 (1H, dd, J=1.5, 7.5 Hz),8.46-8.51(1H, m) 1-38

1.22(6H, t, J=7.2 Hz), 3.51 (2H, s), 4.21(4H, q, J=7.2 Hz), 4.82(2H, s),6.98(1H, br-s), 7.03-7.17(4H, m), 7.22(1H, dd, J=5.0, 8.5 Hz),7.41-7.47(1H, m), 7.48-7.63(5H, m), 7.64- 7.72(2H, m), 7.77-7.83(1H, m),8.50-8.57(2H, m) 1-39

1.04(6H, t, J=7.4 Hz), 3.16-3.29(4H, m), 3.55 (2H, s), 4.84(2H, s),6.75- 6.83(2H, m), 7.04-7.14 (4H, m), 7.17-7.22(2H, m), 7.27-7.35(3H,m), 7.41(1H, dd, J=1.1, 7.6 Hz), 7.47-7.54(2H, m), 7.56(1H, dd, J=1.5,7.6 Hz), 7.61-7.72(3H, m), 8.08(1H, dd, J=1.1, 7.6 Hz) 1-40

1.20(6H, t, J=7.1 Hz), 3.55 (2H, s), 4.21(4H, q, J=7.1 Hz), 4.84(2H, s),7.20- 7.77(16H, m), 8.16(1H, br)

TABLE 9 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-41

1.01(3H, t, J=7.2 Hz), 1.60 (2H, m), 1.96(2H, m), 3.59 (2H, s), 3.84(4H,m), 4.21 (2H, t, J=6.5 Hz), 4.89 (2H, s), 7.00(1H, d, J=8.3 Hz),7.09-7.16(5H, m), 7.32-7.58(8H, m), 8.26 (1H, dd, J=8.0, 1.9 Hz),10.07(1H, br.s) 1-42

0.88(6H, t, J=7.1 Hz), 1.19-1.34(4H, m), 1.35- 1.48(4H, m), 3.16-3.26(4H, m), 3.52(2H, s), 3.16- 3.26(4H, m), 3.52(2H, s), 4.84(2H, s),6.95(1H, br-s), 7.02-7.23(8H, m), 7.27- 7.36(3H, m), 7.40-7.47 (1H, m),7.49-7.63(4H, m), 7.64-7.73(2H, m), 7.81(1H, dd, J=1.5, 7.5 Hz) 1-43

1.22(6H, t, J=7.1 Hz), 3.58 (2H, s), 4.22(4H, q, J=7.1 Hz), 4.95(2H, s),6.23(2H, d, J=8.5 Hz), 7.30-7.73 (10H, m), 7.87(2H, d, J= 8.5 Hz),8.36(1H, dd, J= 6.8, 2.3 Hz), 12.3(1H, brs) 1-44

1.24(6H, t, J=7.1 Hz), 3.58 (2H, s), 4.23(4H, q, J=7.1 Hz), 4.27(2H, s),4.85(2H, s), 7.22(2H, d, J=8.5 Hz), 7.27-7.98(13H, m), 7.61 (2H, d,J=8.5 Hz) 1-45

1.05(6H, t, J=7.3 Hz), 1.69 (3H, s), 3.14-3.30(4H, m), 3.49(2H, s),4.83(2H, s), 6.77(1H, brs), 6.89(1H, brs), 6.92-7.85(17H, m).

TABLE 10 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-46

1.20(6H, t, J=7.1 Hz), 2.38 (3H, s), 3.49(2H, s), 4.19 (4H, q, J=7.1Hz), 4.81 (2H, s), 6.90(1H, brs), 7.05 (4H, brs), 7.19-7.56(12H, m),7.88(1H, d, J=7.1 Hz). 1-47

1.20(6H, t, J=7.1 Hz), 3.49 (2H, s), 3.81(3H, s), 4.19 (4H, q, J=7.1Hz), 4.81 (2H, s), 6.87-7.56(17H, m), 7.86(1H, d, J=7.6 Hz) 1-48

1.12(6H, t, J=7.2 Hz), 2.49-2.58(2H, m), 3.30 (4H, dq, J=5.6, 7.2 Hz),3.54(2H, s), 4.07-4.15(2H, m), 6.94(1H, br-s), 7.11- 7.18(4H, m),7.22-7.37 (5H, m), 7.41-7.46(1H, m), 7.48-7.63(6H, m), 7.65-7.71(2H, m),7.80 (1H, dd, J=1.5, 7.5 Hz) 1-49

0.87(6H, t, J=7.2 Hz), 1.51 (4H, tq, J=7.2, 7.2 Hz), 2.50-2.59(2H, m),3.18-3.27(4H, m), 3.54 (2H, s), 4.07-4.15(2H, m), 6.95(1H, br-s),7.12-7.18 (4H, m), 7.23-7.36(5H, m), 7.41-7.46(1H, m), 7.48-7.63(6H, m),7.65-7.71(2H, m), 7.80 (1H, dd, J=1.5, 7.5 Hz) 1-50

1.05(6H, t, J=7.1 Hz), 3.17-3.28(4H, m), 3.51 (2H, s), 4.82(2H, s), 6.87(1H, br-s), 6.97-7.22(8H, m), 7.27-7.35(3H, m), 7.39-7.59(8H, m), 7.90(1H, dd, J=1.5, 7.5 Hz)

TABLE 11 Exampole Structure NMR (δ, 300 MHz, CDCl₃) 1-51

1.03(6H, t, J=7.1 Hz), 3.16-3.28(4H, m), 3.56 (2H, s), 4.82(2H, s),6.88-6.94(1H, m), 7.02-7.34(13H, m), 7.39-7.49(3H, m), 7.51-7.59(2H, m),8.34 (1H, dd, J=1.9, 7.9 Hz), 9.63(1H, br-s) 1-52

1.05(3H, t, J=7.2 Hz), 1.07(6H, t, J=7.2 Hz), 1.54-1.68(2H, m),1.92-2.05(2H, m), 3.19-3.31(4H, m), 3.58 (2H, s), 4.23(2H, q, J=6.4 Hz),4.85(2H, s), 7.02(1H, d, J=8.3 Hz), 7.06-7.38 (10H, m), 7.44-7.53(1H,m), 7.57-7.65(2H, m), 8.30(1H, dd, J=1.9, 7.9 Hz), 10.08(1H, br-s) 1-53

1.23(6H, t, J=7.1 Hz), 3.53(2H, s), 4.23(4H, q, J=7.1 Hz), 4.84(2H, s),6.95(1H, brs), 7.10(2H, d, J=8.3 Hz), 7.17(2H, d, J=8.3 Hz), 7.32(5H,brs), 7.41-7.87(8H, m). 1-54

1.19(6H, t, J=7.1 Hz), 3.50(2H, s), 4.16(2H, q, J=7.1 Hz), 4.17(2H, q,J=7.1 Hz), 4.80(2H, s), 6.89-7.90(17H, m) 1-55

1.05(6H, t, J=7.2 Hz), 3.19-3.31(4H, m), 3.54 (2H, s), 4.86(2H, s), 6.90(1H, d, J=8.3 Hz), 7.02-7.11 (3H, m), 7.16-7.23(2H, m), 7.25-7.36(4H,m), 7.41 (1H, dd, J=1.2, 7.5 Hz), 7.48-7.61(3H, m), 7.62-7.71(3H, m),8.21 (1H, dd, J=1.5, 7.5 Hz)

TABLE 12 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-56

1.21(6H, t, J=7.1 Hz), 3.51 (2H, s), 4.20(4H, q, J=7.1 Hz), 4.82(2H, s),6.99-7.57 (16H, m), 7.84(1H, d, J= 7.2 Hz). 1-57

1.23(6H, t, J=7.2 Hz), 3.57 (2H, s), 4.22(4H, q, J=7.2 Hz), 4.85(2H, s),7.19-8.08 (19H, m) 1-58

0.94(6H, d, J=6.8 Hz), 1.22 (6H, t, J=7.1 Hz), 3.40(2H, s), 4.20(4H, q,J=7.1 Hz), 4.82(2H, s), 4.99(1H, m), 6.16(1H, br.s), 6.78(2H, d, J=8.6Hz), 7.08(1H, dd, J=8.6, 1.5 Hz), 7.20- 7.74(13H, m) 1-59

0.89(4H, m), 1.22(6H, t, J=7.1 Hz), 1.28-1.78(6H, m), 3.40(2H, s),4.20(4H, q, J=7.1 Hz), 4.62(1H, m), 4.82(2H, s), 6.15(1H, br.s),6.75(2H, m), 7.06-7.74 (14H, m) 1-60

1.23(6H, t, J=6.9 Hz), 1.28(6H, d, J=6.9 Hz), 3.40(1H, sep, J=6.9 Hz),3.56(2H, s), 4.22(4H, q, J= 6.9 Hz), 4.84(2H, s), 7.12- 7.61(14H, m)

TABLE 13 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-61

1.22(6H, t, J=7.1 Hz), 3.53 (2H, s), 4.22(4H, q, J=7.1 Hz), 4.23(2H, s),4.83(2H, s), 6.98-7.61(19H, m) 1-62

0.86(6H, t, J=7.3 Hz), 1.50-1.69(4H, m), 3.50 (2H, s), 4.10(4H, t, J=6.6Hz), 4.83(2H, s), 6.93(1H, brs), 7.08(2H, d, J=8.6 Hz), 7.13(2H, d,J=8.6 Hz), 7.29 (5H, brs), 7.40-7.83(8H, m) 1-63

0.84(12H, d, J=6.6 Hz), 1.80-1.97(2H, m), 3.50 (2H, s), 3.92(4H, d,J=6.6 Hz), 4.84(2H, s), 6.93(1H, brs), 7.08(2H, d, J=5.5 Hz), 7.13(2H,d, J=5.5 Hz), 7.29 (5H, brs), 7.40-7.84(8H, m). 1-64

1.22(6H, t, J=7.1 Hz), 3.57(2H, s), 4.21(4H, q, J=7.1 Hz), 4.84(2H, s),7.21(2H, d, J=8.5 Hz), 7.23- 7.60(8H, m), 7.57(2H, d, J=8.5 Hz),8.09(1H, dd, J=7.8, 1.8 Hz), 8.26 (1H, brs) 1-65

0.84(3H, t, J=7.3 Hz), 1.23 (6H, t, J=7.1 Hz), 1.23- 1.46(2H, m),1.50-1.69 (2H, m), 3.55(2H, s), 4.23(4H, q, J=7.1 Hz), 4.25 (2H, q,J=6.7 Hz), 4.84(2H, s), 7.19(2H, d, J=8.4 Hz), 7.21-7.37(5H, m),7.44-7.64(3H, m), 7.56 (2H, d, J=8.4 Hz), 7.64 (1H, brs), 7.95(1H, d, J=7.6 Hz)

TABLE 14 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-66

0.84(12H, d, J=6.8 Hz), 1.63-1.79(2H, m), 2.97-3.15(4H, m), 3.52 (2H,s), 4.86(2H, s), 6.94 (1H, br-s), 7.01-7.08 (2H, m), 7.10-7.25(6H, m),7.27-7.36(3H, m), 7.40-7.47(1H, m), 7.48-7.63(4H, m), 7.64-7.72(2H, m),7.80 (1H, dd, J=1.5, 8.0 Hz) 1-67

0.87(12H, d, J=6.8 Hz), 1.27-1.38(4H, m), 1.46-1.61(2H, m),3.18-3.28(4H, m), 3.52 (2H, s), 4.84(2H, s), 6.94 (1H, br-s),7.01-7.22(8H, m), 7.27-7.35(3H, m), 7.41-7.47(1H, m), 7.49-7.63(4H, m),7.65-7.72(2H, m), 7.80 (1H, dd, J=1.5, 7.5 Hz) 1-68

1.07(3H, t, J=7.2 Hz), 1.22(6H, t, J=7.1 Hz), 3.40(2H, s), 3.72(2H, q,J=7.2 Hz), 4.20 (4H, q, J=7.1 Hz), 4.83 (2H, s), 6.14(2H, d, J=8.3 Hz),6.74(2H, d, J=8.3 Hz), 7.07(1H, dd, J=9.1, 1.5 Hz), 7.23-7.61(12H, m)1-69

1.09(6H, t, J=7.1 Hz), 1.26-1.50(6H, m), 1.81 (4H, m), 2.99(1H, m),3.26(4H, dq, J=7.1, 7.1 Hz), 3.59(2H, s), 4.85(2H, s), 7.10-7.42(14H,m), 7.56 (2H, d, J=8.3 Hz) 1-70

1.05(6H, t, J=7.2 Hz), 3.18-3.30(4H, m), 3.53 (2H, s), 4.83(2H, s), 6.93(1H, br-s), 7.02-7.23(8H, m), 7.27-7.36(3H, m), 7.37-7.45(5H, m),7.45-7.59(2H, m), 7.80 (1H, dd, J=1.1, 7.5 Hz)

TABLE 15 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-71

1.05(6H, t, J=7.2 Hz), 3.18-3.30(4H, m), 3.54 (2H, s), 4.84(2H, s),7.02- 7.14(5H, m), 7.17-7.35 (8H, m), 7.37-7.62(5H, m), 7.74(1H, dd,J=1.5, 7.5 Hz) 1-72

0.85(6H, t, J=7.5 Hz), 1.44(4H, tq, J=7.5, 7.5 Hz), 1.68(3H, s), 3.12-3.22(4H, m), 3.49(2H, s), 4.85(2H, s), 6.77(1H, br-s), 6.87-6.92(1H, m),6.94-7.01(1H, m), 7.11-7.25(4H, m), 7.27-7.36(3H, m), 7.40-7.47(1H, m),7.50-7.73(6H, m), 7.75-7.85(2H, m) 1-73

3.29(6H, s), 3.36-3.48 (8H, m), 3.53(2H, s), 4.85 (2H, s), 6.97(1H,br-s), 7.04-7.18(4H, m), 7.19- 7.40(8H, m), 7.41-7.47 (1H, m),7.49-7.64(4H, m), 7.66-7.73(2H, m), 7.77-7.84(1H, m) 1-74

1.22(6H, t, J=7.1 Hz), 2.78(3H, s), 3.52(2H, s), 4.21(4H, q, J=7.1 Hz),4.82(2H, s), 7.11(2H, d, J= 8.5 Hz), 7.19(2H, d, J=8.5 Hz),7.20-7.35(6H, m), 7.77(2H, d, J=8.3 Hz), 7.86(2H, d, J=8.3 Hz) 1-75

1.06(6H, t, J=7.3 Hz), 2.78(3H, s), 3.20-3.29(4H, m), 3.55(2H, s),4.84(2H, s), 6.98-7.34(12H, m), 7.77(2H, d, J=8.3 Hz), 7.86(2H, d, J=8.3Hz)

TABLE 16 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-76

1.06(6H, t, J=7.3 Hz), 3.19-3.28(4H, m), 3.54 (2H, s), 4.83(2H, s),6.99- 7.48(13H, m), 7.71(2H, d, J=8.2 Hz), 7.86(2H, d, J=8.2 Hz),8.05-8.13(1H, m), 8.75-8.84(1H, m) 1-77

1.06(6H, t, J=7.2 Hz), 1.64(3H, s), 3.12-3.33 (4H, m), 3.51(2H, s), 4.84(2H, s), 6.84(1H, brs), 6.91 (1H, brs), 6.98-7.98(12H, m), 8.16(1H, d,J=8.1 Hz), 8.84(1H, d, J=4.4 Hz). 1-78

0.92(3H, t, J=7.5 Hz), 1.20(6H, t, J=7.1 Hz), 1.94 (2H, q, J=7.5 Hz),3.50(2H, s), 4.20(4H, q, J=7.1 Hz), 4.82(2H, s), 6.79-7.83 (17H, m) 1-79

0.96(6H, d, J=6.6 Hz), 1.05(6H, t, J=7.1 Hz), 2.15 (1H, sep, J=6.6 Hz),3.19- 3.29(4H, m), 3.54(2H, s), 4.83(2H, s), 6.81-7.84 (19H, m) 1-80

0.96(6H, d, J=6.8 Hz), 1.20(6H, t, J=7.1 Hz), 2.16 (1H, sep, J=6.8 Hz),4.20 (4H, q, J=7.1 Hz), 4.82 (2H, s), 6.79-7.82(17H, m)

TABLE 17 Example Structure NMR (δ, 300 MHz, CDCl₃) 1-81

0.95(3H, t, J=7.7 Hz), 1.13 (6H, t, J=7.2 Hz), 1.99(2H, q, J=7.7 Hz),2.54(2H, t, J=7.9 Hz), 3.20-3.38 (4H, m), 3.53(2H, s), 4.11 (2H, t,J=7.9 Hz), 6.79- 7.84(19H, m) 1-82

0.72(6H, d, J=6.6 Hz), 1.06 (6H, t, J=7.2 Hz), 1.26- 1.44(1H, m),1.89(2H, d, J=7.3 Hz), 3.20-3.27(4H, m), 3.52(2H, s), 4.83(2H, s),6.82-7.88(19H, m) 1-83

0.71(6H, d, J=6.5 Hz), 1.21 (6H, t, J=7.1 Hz), 1.26- 1.43(1H, m),1.88(2H, d, J=7.3 Hz), 3.49(2H, s), 4.21(4H, q, J=7.1 Hz), 4.83(2H, s),6.79-7.87 (17H, m) 1-84

1.21(6H, t, J=7.2 Hz), 3.48 (2H, s), 4.22(4H, q, J=7.2 Hz), 4.83(2H, s),7.08(1H, d, J=8.7 Hz), 7.12(1H, s), 7.25-7.67(13H, m), 7.84 (1H, dd,J=1.5, 7.5 Hz), 8.37(1H, d, J=8.7 Hz) 1-85

1.21(6H, t, J=7.1 Hz), 3.48 (2H, s), 4.22(4H, q, J=7.1 Hz), 4.83(2H, s),7.13(1H, d, J=7.9 Hz), 7.28-7.67 (14H, m), 7.82(1H, dd, J= 1.5, 7.5 Hz),8.35(1H, d, J=8.7 Hz)

Example 2{3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester a)5-Chloro-N,N-dimethyl-2-nitrobenzamide

The acid chloride obtained from 5-chloro-2-nitrobenzoic acid (5.0 g) ina similar manner to Example 1d) was subjected to reactions similar tothose in Example 1e) to give the title compound (5.5 g).

b) 2-(3-Dimethylcarbamoyl-4-nitrophenyl)malonic acid tert-butyl estermethyl ester

Sodium hydride (350 mg) was dissolved in dimethylformamide (10 mL)), andthe solution was cooled to 0° C. After addition of tert-butyl methylmalonate (1.52 g), the mixture was stirred for one hour, and the5-chloro-N,N-dimethyl-2-nitrobenzamide (1.0 g) obtained in Example 2a)was added thereto. The mixture was stirred at 70° C. for 4.5 hours andwater was added thereto. The resulting solution was concentrated,diluted with ethyl acetate and washed with water. The organic layer wasdried over sodium sulfate and purified by column chromatography onsilica gel with ethyl acetate:hexane=1:1 to give the title compound(1.29 g).

c) (3-Dimethylcarbamoyl-4-nitrophenyl)acetic acid methyl ester

The 2-(3-dimethylcarbamoyl-4-nitrophenyl)malonic acid tert-butyl estermethyl ester (1.22 g) obtained in Example 2b) was dissolved indichloromethane (10 mL), and the solution was cooled to 0° C. Afteraddition of trifluoroacetic acid (10 mL), the mixture was stirred atroom temperature for 6 hours, and concentrated, followed by azeotropicdistillation with toluene. The residue was purified by columnchromatography on silica gel with ethyl acetate:hexane=3:1 to give thetitle compound (712 mg).

d) (4-Amino-3-dimethylcarbamoylphenyl)acetic acid methyl ester

The (3-dimethylcarbamoyl-4-nitrophenyl)acetic acid methyl ester (683 mg)obtained in Example 2c) was subjected to reactions similar to those inExample 1-3d) to give the title compound (627 mg).

e){3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid

The (4-amino-3-dimethylcarbamoylphenyl)acetic acid methyl ester (627 mg)obtained in Example 2d) was subjected to reactions similar to those inExample 1e) and Example 1f) to give the title compound (1.07 g)(seeTable 65).

f){3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester

The{3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}aceticacid (517 mg) obtained in Example 2e) was subjected to reactions similarto those in Example 1g) to give the title compound (387 mg) (see Table18).

Examples 2-2 to 2-119

Compounds of Examples 2-2 to 2-119 were obtained in a similar manner toExample 2. The compounds thus obtained were shown in Tables 18 to 41. Inaddition, compound of Example 2-17e) was obtained in a similar manner toExample 2e) and the compounds thus obtained were shown in Table 65.

TABLE 18 Example Structure NMR (δ, 300 MHz, CDCl₃) 2

1.07(6H, t, J=7.2 Hz), 2.85(3H, br.s), 2.95(3H, br.s), 3.26(4H, dq,J=7.2, 7.2 Hz), 3.54(2H, s), 4.84(2H, s), 7.04-7.68(17H, m), 8.37(1H, d,J=8.3 Hz), 9.16(1H, br.s) 2-2

0.86(6H, t, J=7.2 Hz), 1.46(4H, tq, J=7.2, 7.2 Hz), 2.85(3H, br.s),2.95(3H, br.s), 3.19(4H, dt, J=7.2, 7.2 Hz), 3.54(2H, s), 4.85(2H, s),7.03-7.68(17H, m), 8.37(1H, d, J=8.7 Hz), 9.17(1H, br.s) 2-3

1.07(6H, t, J=7.1 Hz), 2.83(3H, d, J=4.5 Hz), 3.24(4H, dq, J=7.1, 7.1Hz), 3.59(2H, s), 4.80(2H, s), 7.10-7.76(18H, m), 8.53(1H, d, J=8.3 Hz),11.55(1H, br.s) 2-4

1.12(6H, t, J=J=7.3 Hz), 2.53(2H, t, J=7.7 Hz), 2.86(3H, brs), 2.95(3H,brs), 3.20-3.40(4H, m), 3.54(2H, s), 4.12(2H, t, J=7.7 Hz), 7.09(1H,brs), 7.17-7.45(14H, m), 8.36(1H, d, J=8.4 Hz), 9.24(1H, brs). 2-5

1.21(6H, t, J=7.1 Hz), 2.81(3H, brs), 2.92(3H, brs), 3.50(2H, s),4.20(4H, q, J=7.1 Hz), 4.82(2H, s), 6.99(1H, brs), 7.17-7.71(14H, m),8.33(1H, d, J=8.5 Hz), 9.14(1H, brs).

TABLE 19 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-6 

0.98(6H, t, J=7.3 Hz), 3.12(4H, dq, J=7.3, 7.3 Hz), 3.58(2H, s),4.50(2H, d, J=5.9 Hz), 4.79(2H, s), 7.01-7.59(16H, m), 7.72(1H, dd,J=7.0, 1.8 Hz), 8.23(1H, m), 8.51(1H, d, J=8.5 Hz), 11.49(1H, br.s) 2-7 

1.07(6H, t, J=7.3 Hz), 1.66(2H, m), 2.28(2H, m), 2.87(3H, br.s),2.93(3H, br.s), 3.24(4H, dq, J=7.3, 7.3 Hz), 3.57(2H, s), 4.11(2H, t,J=6.9 Hz), 7.13-7.66(17H, m), 8.36(1H, d, J=8.4 Hz), 9.08(1H, br.s) 2-8 

1.08(6H, t, J=7.2 Hz), 0.98-1.21(6H, brd), 3.26(4H, dq, J=7.2, 7.2 Hz),3.12-3.51(4H, brd), 3.56(2H, s), 4.84(2H, s), 7.06-7.63(17H, m),8.21(1H, d, J=8.7 Hz), 8.88(1H, s) 2-9 

1.07(6H, t, J=7.1 Hz), 0.93-1.59(6H, brd), 3.26(4H, dq, J=7.2, 7.2 Hz),3.56(2H, s), 3.41- 3.95(2H, brd), 4.84(2H, s), 7.01-7.62(17H, m),8.08(1H, d, J=8.3 Hz), 8.70(1H, br.s) 2-10

1.21(6H, t, J=7.1 Hz), 0.95-1.27(6H, brd), 3.08-3.49(4H, brd), 3.52(2H,s), 4.21(4H, q, J=7.1 Hz), 4.83(2H, s), 7.06(1H, d, J=1.9 Hz), 7.19(1H,dd, J=8.7, 1.9 Hz), 7.31-7.63(13H, m), 8.19(1H, d, J=8.7 Hz), 8.90(1H,br.s)

TABLE 20 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-11

1.21(6H, t, J=7.1 Hz), 1.00-1.52(12H, brd), 3.52(2H, s), 3.49-3.92(2H,brd), 4.20(4H, q, J=7.1 Hz), 4.82(2H, s), 7.02(1H, d, J=1.9 Hz),7.17(1H, dd, J=8.4, 1.9 Hz), 7.31-7.64(13H, m), 8.06 (1H, d, J=8.4 Hz),8.72 (1H, br.s) 2-12

1.01-1.21(6H, m), 1.07(6H, t, J=7.3 Hz), 2.78(3H, brs), 3.20-3.31(4H,m), 3.56 (2H, s), 3.82-4.27(1H, m), 4.84(2H, s), 6.99-7.63 (17H, m),8.19(1H, d, J= 8.4 Hz), 8.98(1H, br.s) 2-13

0.98-1.27(3H, br), 1.21 (6H, t, J=7.1 Hz), 2.73- 2.96(3H, br), 3.05-3.49(2H, br), 3.51(2H, s), 4.21(4H, q, J=7.1 Hz), 4.82(2H, s), 7.00-7.08(1H,m), 7.19(1H, dd, J=1.9, 8.3 Hz), 7.24-7.36(5H, m), 7.39(1H, dd, J=1.5,7.9 Hz), 7.43-7.70(7H, m), 8.28(1H, d, J=8.6 Hz), 8.92-9.18(1H, br) 2-14

1.00-1.23(3H, br), 1.08 (6H, t, J=7.2 Hz), 2.79- 2.96(3H, br), 3.10-3.49(2H, br), 3.26(4H, dq, J=5.2, 7.2 Hz), 3.55(2H, s), 4.84(2H, s),7.04(1H, d, J=1.8 Hz), 7.07-7.14 (2H, m), 7.15-7.24(3H, m),7.28-7.37(3H, m), 7.37- 7.43(1H, m), 7.44-7.69 (7H, m), 8.30(1H, d, J=8.3 Hz), 8.88-9.17(1H, br) 2-15

1.02-1.24(3H, br), 1.12 (6H, t, J=7.2 Hz), 2.47- 2.59(2H, m), 2.80-2.96(3H, br), 3.10-3.51(2H, br), 3.30(4H, dq, J=5.7, 7.2 Hz), 3.55(2H, s),4.07- 4.18(2H, m), 7.09(1H, d, J=1.5 Hz), 7.22-7.43(7H, m),7.43-7.70(9H, m), 8.28 (1H, d, J=8.3 Hz), 8.85- 9.14(1H, br)

TABLE 21 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-16

1.07(6H, t, J=7.2 Hz), 1.32-1.71(5H, br), 3.10-3.79(8H, m), 3.54 (2H,s), 4.84(2H, s), 7.03- 7.79(15H, m), 8.28(1H, d, J=8.5 Hz), 9.04(1H,brs). 2-17

1.07(6H, t, J=7.2 Hz), 2.02-2.78(4H, br), 3.21-3.53(8H, m), 3.54 (2H,m), 4.84(2H, s), 7.03- 7.72(15H, m), 8.34(1H, d, J=7.2 Hz), 9.83(1H,brs). 2-18

0.65-1.01(3H, br), 1.21 (6H, t, J=7.2 Hz), 1.43- 1.66(2H, br), 2.75-2.98(3H, br), 3.05-3.41(2H, br), 3.51(2H, s), 4.21(4H, q, J=7.2 Hz),4.82(2H, s), 7.04(1H, br-s), 7.19(1H, dd, J=1.9, 8.6 Hz), 7.24- 7.35(5H,m), 7.39(1H, dd, J=1.5, 7.5 Hz), 7.43- 7.69(7H, m), 8.18-8.31 (1H, br),8.94-9.18(1H, br) 2-19

0.68-0.99(3H, br), 1.08 (6H, t, J=7.1 Hz), 1.42- 1.69(2H, br), 2.79-2.98(3H, br), 3.06-3.42(2H, br), 3.26(4H, dq, J=5.6, 7.1 Hz), 3.55(2H, s),4.84(2H, s), 7.04(1H, d, J=1.8 Hz), 7.11(2H, br-t, J=5.6 Hz),7.15-7.24(3H, m), 7.27- 7.36(3H, m), 7.37-7.43 (1H, m), 7.44-7.69(7H,m), 8.21-8.35(1H, br), 8.92-9.18(1H, br) 2-20

0.67-1.00(3H, br), 1.13 (6H, t, J=7.1 Hz), 1.43- 1.67(2H, br), 2.48-2.59(2H, m), 2.82-2.98(3H, br), 3.06-3.42(2H, br), 3.30(4H, dq, J=5.6, 7.1Hz), 3.54(2H, s), 4.07-4.17 (2H, m), 7.09(1H, d, J=2.2 Hz),7.22-7.42(7H, m), 7.43-7.69(9H, m), 8.20- 8.34(1H, br), 8.89-9.14 (1H,br)

TABLE 22 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-21

1.04(3H, t, J=7.2 Hz), 2.84 (3H, brs), 2.95(3H, brs), 3.16-3.29(2H, m),3.50 (2H, s), 3.64(1H, dd, J=7.7, 6.5 Hz), 3.91(1H, dd, J= 10.9, 6.5Hz), 4.64(1H, dd, J=10.9, 7.7 Hz), 5.28- 5.38(1H, m), 7.00-7.71 (15H,m), 8.34(1H, d, J= 8.5 Hz), 9.15(1H, brs) 2-22

1.21(6H, t, J=7.1 Hz), 1.73-2.00(4H, m), 3.22-3.53(4H, m), 3.51 (2H, s),4.20(4H, q, J= 7.1 Hz), 4.83(2H, s), 7.15- 7.70(15H, m), 8.33(1H, d,J=8.9 Hz), 9.84(1H, brs). 2-23

1.21(6H, t, J=7.1 Hz), 1.35-1.70(6H, br), 3.00-3.76(4H, br), 3.51 (2H,s), 4.20(4H, q, J= 7.1 Hz), 4.82(2H, s), 7.03 (1H, d, J=2.0 Hz), 7.12-7.68(14H, m), 8.26(1H, d, J=8.5 Hz), 9.06(1H, brs). 2-24

1.11(3H, t, J=7.6 Hz), 2.19(2H, q, J=7.6 Hz), 2.84 (3H, brs), 2.95(3H,brs), 3.54(2H, s), 4.28(1H, dd, J=11.3, 4.9 Hz), 4.41(1H, dd, J=11.3,7.0 Hz), 5.25- 5.33(1H, m), 5.87(1H, d, J=8.3 Hz), 7.04-7.71(15H, m),8.36(1H, d, J=8.5 Hz), 9.14(1H, brs) 2-25

1.11(3H, t, J=7.5 Hz), 2.19(2H, q, J=7.5 Hz), 2.84 (3H, brs), 2.95(3H,brs), 3.54(2H, s), 4.29(1H, dd, J=11.3, 4.9 Hz), 4.41(1H, dd, J=11.3,7.0 Hz), 5.26- 5.33(1H, m), 5.86(1H, d, J=7.9 Hz), 7.04-7.71(15H, m),8.36(1H, d, J=8.7 Hz), 9.14(1H, brs)

TABLE 23 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-26

2.53(4H, s), 2.89(3H, brs), 2.96(3H, brs), 3.55(2H, s), 4.66(1H, dd,J=10.9, 5.3 Hz), 5.10(1H, t, J=10.9 Hz), 5.37(1H, dd, J=10.9, 5.3 Hz),7.07-7.69(15H, m), 8.35(1H, d, J=8.7 Hz), 9.17(1H, brs) 2-27

1.19(3H, t, J=7.2 Hz), 2.70-3.01(6H, br), 3.41(2H, dq, J=5.6, 7.2 Hz),3.60(2H, s), 5.32(2H, s), 6.18(1H, br-t, J=5.6 Hz), 7.04(1H, d, J=1.9Hz), 7.21-7.29(1H, m), 7.30-7.56(7H, m), 7.56-7.66(4H, m), 7.69 (1H, dd,J=1.5, 7.1 Hz), 8.35(1H, d, J=8.7 Hz), 9.09(1H, br-s) 2-28

1.04(3H, t, J=7.1 Hz), 2.70-3.00(6H, br), 3.22(2H, dq, J=5.7, 7.1 Hz),3.53(2H, s), 3.57(2H, s), 5.13(2H, s), 5.43- 5.54(1H, br), 7.08(1H, d,J=1.9 Hz), 7.21-7.43(6H, m), 7.44-7.66(6H, m), 7.69(1H, dd, J=1.5, 7.2Hz), 8.34(1H, d, J=8.6 Hz), 9.10(1H, br-s) 2-29

1.26-1.68(6H, m), 2.61-3.00(6H, m), 2.93-3.12(1H, m), 3.58-4.01(1H, m),4.28-5.03(3H, m), 7.09-8.32(17H, m), 9.14 (1H, brs), 9.40-10.24(2H, m)2-30

1.10(6H, t, J=7.3 Hz), 3.06 (6H, brs), 3.21-3.42(4H, m), 3.61(2H, s),4.86(2H, s), 7.06-7.77(13H, m), 8.37 (1H, d, J=8.5 Hz), 9.21 (1H, brs)

TABLE 24 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-31

1.23(6H, t, J=7.1 Hz), 2.98 (3H, brs), 3.05(3H, brs), 4.22(4H, q, J=7.1Hz), 4.85 (2H, s), 7.11-7.75(11H, m), 8.35(1H, d, J=8.5 Hz), 9.21(1H,brs) 2-32

1.24(6H, t, J=7.2 Hz), 2.61 (2H, t, J=7.1 Hz), 2.86(3H, br.s), 2.94(3H,br.s), 3.46 (2H, s), 4.07(2H, t, J=7.1 Hz), 4.23(4H, q, J=7.21 Hz),7.08(1H, d, J=1.9 Hz), 7.23-7.68(14H, m), 8.36 (1H, d, J=8.6 Hz),9.15(1H, br.s) 2-33

1.22(6H, t, J=7.2 Hz), 2.83 (3H, br.s), 2.94(3H, br.s), 3.51(2H, s),4.21(4H, q, J= 7.2 Hz), 4.83(2H, s), 7.00- 7.51(14H, m), 7.68(1H, dd,J=7.6, 1.5 Hz), 8.37(1H, d, J=8.3 Hz), 8.93(1H, br.s) 2-34

1.22(6H, t, J=7.2 Hz), 2.86 (3H, br.s), 2.95(3H, br.s), 3.51(2H, s),4.21(4H, q, J= 7.2 Hz), 4.83(2H, s), 7.01 (1H, d, J=2.2 Hz), 7.19-7.53(13H, m), 7.68(1H, dd, J=7.6, 1.5 Hz), 8.40(1H, d, J=8.3 Hz),9.01(1H, br.s) 2-35

1.96(3H, s), 2.84(3H, brs), 2.95(3H, brs), 3.54(2H, s), 4.29(1H, dd,J=11.6, 5.0 Hz), 4.39(1H, dd, J=11.6, 7.1 Hz), 5.23-5.33(1H, m),5.90(1H, d, J=8.1 Hz), 6.99-7.71(15H, m), 8.36 (1H, d, J=8.5 Hz),9.14(1H, brs)

TABLE 25 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-36

0.92(3H, t, J=7.4 Hz), 1.56-1.68(2H, m), 2.14(2H, t, J=7.5 Hz), 2.84(3H,brs), 2.95(3H, brs), 3.54 (2H, s), 4.29(1H, dd, J= 11.4, 4.9 Hz),4.40(1H, dd, J=11.4, 7.1 Hz), 5.23-5.33(1H, m), 5.90 (1H, d, J=8.1 Hz),7.05 (1H, d, J=2.0 Hz), 7.15- 7.72(14H, m), 8.36(1H, d, J=8.5 Hz),9.15(1H, brs) 2-37

1.07(3H, t, J=7.3 Hz), 1.08(3H, t, J=7.3 Hz), 2.97(3H, s), 3.10(3H, s),3.18-3.31(4H, m), 3.59(2H, s), 4.87(2H, d, J=4.1 Hz), 6.38(1H, d, J=8.2Hz), 6.92-7.64(18H, m), 7.83(1H, d, J=6.8 Hz) 2-38

1.21(6H, t, J=7.1 Hz), 2.96(3H, s), 3.07(3H, s), 3.55(2H, d, J=2.1 Hz),4.19 (2H, q, J=7.1 Hz), 4.20 (2H, q, J=7.1 Hz), 4.82 and 4.89(2H, eachd, J=11.2 Hz), 6.36(1H, d, J=8.2 Hz), 6.93-7.59(16H, m), 7.83 (1H, d,J=6.8 Hz) 2-39

2.73-3.00(6H, br), 3.52 (2H, s), 3.72(6H, s), 4.82 (2H, s), 7.03(1H, d,J=1.9 Hz), 7.16-7.36(6H, m), 7.40(1H, dd, J=1.5, 7.5 Hz), 7.45-7.65(6H,m), 7.69(1H, dd, J=1.5, 7.2 Hz), 8.35(1H, d, J=8.7 Hz), 9.17(1H, br-s)2-40

1.21(6H, t, J=7.1 Hz), 1.31-1.60(6H, m), 1.67-1.82(2H, m), 2.40-2.57(1H,m), 2.88 (3H, brs), 2.94(3H, brs), 3.53(2H, s), 4.14(4H, q, J= 7.1 Hz),4.48(2H, s), 7.09 (1H, d, J=1.8 Hz), 7.2- 7.72(9H, m), 8.37(1H, d, J=8.4Hz), 9.16(1H, brs).

TABLE 26 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-41

0.95-1.19(6H, m), 1.21 (6H, t, J=9.5 Hz), 1.60- 1.80(4H, m), 2.00-2.18(1H, m), 2.88(3H, brs), 2.95(3H, brs), 3.52(2H, s), 4.14(4H, q, J=9.5Hz), 4.50(2H, s), 7.09(1H, d, J=2.7 Hz), 7.19-7.73(9H, m), 8.38(1H, d,J=11.3 Hz), 9.18(1H, brs). 2-42

1.22(6H, t, J=7.2 Hz), 2.84(3H, br.s), 2.94(3H, br.s), 3.51(2H, s), 4.21(4H, q, J=7.2 Hz), 4.83 (2H, s), 7.01(1H, d, J= 1.9 Hz), 7.20(1H, dd, J=8.7, 1.9 Hz), 7.26-7.51 (12H, m), 7.68(1H, dd, J= 7.5, 1.5 Hz), 8.40(1H,d, J=8.7 Hz), 9.00(1H, br.s) 2-43

1.21(6H, t, J=7.2 Hz), 2.57(3H, s), 2.75(3H, br.s), 2.94(3H, br.s),3.50(2H, s), 4.20(4H, q, J=7.2 Hz), 4.82 (2H, s), 7.00(1H, d, J= 1.9Hz), 7.18(1H, dd, J= 8.6, 1.9 Hz), 7.26-7.59 (11H, m), 7.70(1H, dd, J=7.6, 1.5 Hz), 7.95(1H, d, J=8.3 Hz), 8.35(1H, d, J=8.6 Hz), 9.13(1H,br.s) 2-44

1.07(6H, t, J=7.3 Hz), 2.76(3H, s), 2.86(3H, s), 3.21-3.30(4H, m), 3.57(2H, s), 4.83(2H, s), 6.82 (1H, d, J=8.3 Hz), 6.98- 7.45(16H, m),8.24(1H, dd, J=7.8, 1.8 Hz), 8.44 (1H, d, J=8.5 Hz), 10.4 (1H, brs) 2-45

1.22(6H, t, J=7.1 Hz), 2.75(3H, s), 2.82(3H, s), 3.54(2H, s), 4.21(4H,q, J= 7.1 Hz), 4.83(2H, s), 6.82 (1H, d, J=7.6 Hz), 7.05(1H, d, J=2.0Hz), 7.09-7.46 (13H, m), 8.24(1H, dd, J= 7.8, 1.8 Hz), 8.42(1H, d, J=8.5Hz), 10.4(1H, brs)

TABLE 27 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-46

1.22(6H, t, J=7.2 Hz), 2.90 (3H, br.s), 2.97(3H, br.s), 3.52(2H, s),4.21(4H, q, J=7.2 Hz), 4.83(2H, s), 7.05(1H, d, J=1.9 Hz), 7.20 (1H, dd,J=8.7, 1.9 Hz), 7.29-7.73(13H, m), 8.33 (1H, d, J=8.7 Hz), 9.27 (1H,br.s) 2-47

1.21(6H, t, J=7.2 Hz), 2.44 (3H, s), 2.77(3H, br.s), 2.91(3H, br.s),3.50(2H, s), 4.20(4H, q, J=7.2 Hz), 4.82 (2H, s), 7.01(1H, d, J=2.2 Hz),7.19(1H, dd, J=8.7, 2.2 Hz), 7.30-7.59(12H, m), 8.35(1H, d, J=8.7 Hz),9.08(1H, br.s) 2-48

1.21(6H, t, J=7.1 Hz), 2.44 (3H, s), 2.80(3H, br.s), 2.94(3H, br.s),3.50(2H, s), 4.20(4H, q, J=7.1 Hz), 4.82 (2H, s), 7.02(1H, d, J=2.2 Hz),7.16-7.30(8H, m), 7.56-7.63(5H, m), 8.35 (1H, d, J=8.7 Hz), 9.14 (1H,br.s) 2-49

2.65(3H, s), 2.86(3H, brs), 2.95(3H, brs), 3.61(2H, s), 4.23-4.30(2H,m), 4.71-4.79(1H, m), 4.98 ((1H, d, J=7.1 Hz), 7.09 (1H, d, J=1.9 Hz),7.18- 7.71(14H, m), 8.37(1H, d, J=8.7 Hz), 9.16(1H, brs) 2-50

1.19(3H, t, J=7.1 Hz), 2.86 (3H, brs), 2.95(3H, brs), 3.52(2H, s),3.89(1H, dd, J=9.1, 6.0 Hz), 4.02- 4.19(2H, m), 4.34(1H, dd, J=10.9, 6.0Hz), 4.58(1H, dd, J=10.9, 9.1 Hz), 7.06 (1H, d, J=2.3 Hz), 7.18-7.71(14H, m), 8.36(1H, d, J=8.6 Hz), 9.17(1H, brs)

TABLE 28 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-51

1.12-1.18(3H, m), 2.21-2.46(2H, m), 2.64-3.49(9H, m), 3.55-3.58(2H, m),4.45-5.29(2H, m), 6.11-6.19(1H, m), 7.12-7.70(15H, m), 8.33-8.38(1H, m),9.17 (1H, brs) Conformer 2-52

1.24(6H, t, J=7.0 Hz), 1.50-1.64(2H, m), 2.25- 2.36(2H, m), 2.77-3.02(6H, br), 3.54(2H, s), 3.99- 4.08(2H, m), 4.16-4.29 (4H, m), 7.10(1H, d,J= 1.9 Hz), 7.24-7.43(7H, m), 7.44-7.57(2H, m), 7.59-7.64(4H, m), 7.68(1H, dd, J=1.5, 7.2 Hz), 8.36(1H, d, J=8.7 Hz), 9.16 (1H, s) 2-53

1.21(6H, t, J=7.0 Hz), 2.82(3H, br.s), 2.95(3H, br.s), 3.50(2H, s),3.88(3H, s), 4.21(4H, q, J=7.0 Hz), 4.82(2H, s), 6.87(1H, d, J= 2.6 Hz),6.99(1H, dd, J= 8.5, 2.6 Hz), 7.03(1H, d, J= 1.8 Hz), 7.18(1H, dd, J=8.5, 1.8 Hz), 7.29-7.69 (10H, m), 8.35(1H, d, J= 8.8 Hz), 9.17(1H, br.s)2-54

1.21(6H, t, J=7.0 Hz), 2.81(3H, br.s), 2.94(3H, br.s), 3.51(2H, s),4.20(4H, q, J=7.0 Hz), 4.83(2H, s), 7.04(1H, d, J=2.2 Hz), 7.19 (1H, dd,J=8.4, 2.2 Hz), 7.30-7.66(12H, m), 8.33 (1H, d, J=8.5 Hz), 9.29 (1H,br.s) 2-55

1.20(6H, t, J=7.1 Hz), 2.11(3H, s), 2.88(3H, brs), 3.04(3H, brs),3.48(2H, s), 4.19(4H, q, J=7.1 Hz), 4.81 (2H, s), 7.04(1H, d, J=2.0 Hz),7.12(1H, dd, J=2.0 Hz, J=8.5 Hz), 7.24- 7.50(10H, m), 7.60(2H, d, J=8.1Hz), 8.10(1H, d, J=8.5 Hz), 9.06(1H, brs).

TABLE 29 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-56

2.81(3H, brs), 2.93(3H, brs), 3.52(2H, s), 4.45- 4.60(4H, m), 4.88(2H,s), 7.02(1H, d, J=2.0 Hz), 7.19 (1H, dd, J=2.0 Hz), J= 8.7 Hz),7.23-7.64(12H, m), 7.68(1H, dd, J=2.0 Hz, J=8.1 Hz), 8.34(1H, d, J=8.1Hz), 9.10(1H, brs). 2-57

1.21(6H, t, J=7.1 Hz), 2.95 (3H, brs), 3.01(3H, brs), 3.52(2H, s),4.21(4H, q, J= 7.1 Hz), 4.83(2H, s), 7.10 (1H, s), 7.14-7.63(12H, m),7.75((1H, d, J=6.6 Hz), 8.22(1H, d, J=8.7 Hz), 9.34(1H, brs). 2-58

1.23(6H, t, J=7.1 Hz), 2.85 (6H, br-s), 3.55(2H, s), 4.22(4H, q, J=7.1Hz), 4.83 (2H, s), 7.03((1H, d, J= 7.6 Hz), 7.24-7.74(13H, m), 8.36(1H,d, J=12.2 Hz), 9.45(1H, br-s). 2-59

1.22(6H, t, J=7.1 Hz), 2.87 (3H, s), 2.96(3H, s), 3.51 (2H, s), 4.22(4H,q, J=7.1 Hz), 4.85(2H, s), 7.06(1H, brs), 7.25-7.68(14H, m), 7.77(1H, d,J=7.1 Hz). 2-60

1.22(6H, t, J=7.1 Hz), 2.86 (3H, brs), 2.95(3H, s), 3.50(2H, s),4.22(4H, q, J=7.1 Hz), 4.85(2H, s), 7.00(1H, d, J=1.5 Hz),7.20-7.66(13H, m), 7.73 (1H, dd, J=1.5 Hz, J=7.1 Hz), 7.97(1H, brs).

TABLE 30 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-61

1.21(6H, t, J=7.2 Hz), 2.88 (3H, brs), 2.97(3H, brs), 3.52(2H, s),4.20(4H, q, J= 7.2 Hz), 4.83(2H, s), 7.07 (1H, d, J=2.2 Hz), 7.18-7.72(13H, m), 8.33(1H, d, J=8.4 Hz), 9.33(1H, brs). 2-62

1.21(6H, t, J=7.1 Hz), 2.87 (3H, brs), 2.96(3H, brs), 3.52(2H, s),4.21(4H, q, J= 7.1 Hz), 4.83(2H, s), 7.07 (1H, d, J=1.8 Hz), 7.17-7.72(13H, m), 8.32(1H, d, J=8.4 Hz), 9.32(1H, br-s). 2-63

1.22(6H, t, J=7.2 Hz), 2.83 (3H, brs), 2.94(3H, brs), 3.48(2H, s),4.23(4H, q, J= 7.21 Hz), 4.94(2H, s), 6.98 (1H, d, J=1.9 Hz), 7.12-7.76(10H, m), 8.30(1H, d, J=8.3 Hz), 8.38(1H, dd, J=2.6 Hz, J=8.9 Hz),9.08 (1H, brs), 9.22(1H, d, J= 2.6 Hz). 2-64

1.21(6H, t, J=7.2 Hz), 2.83 (3H, brs), 2.94(3H, brs), 3.48(2H, s),3.49(1H, brs), 3.71(1H, brs), 4.20(4H, q, J=7.2 Hz), 4.88(2H, s),6.83(1H, dd, J=3.0 Hz), J=8.3 Hz), 7.03(1H, d, J= 1.9 Hz),7.11-7.72(10H, m), 7.83(1H, d, J=3.1 Hz), 8.25(1H, d, J=8.6 Hz), 9.14(1H, brs). 2-65

1.21(6H, t, J=7.2 Hz), 2.83 (3H, brs), 2.93(3H, brs), 3.49(2H, s),4.21(4H, q, J= 7.2 Hz), 4.93(2H, s), 7.03 (1H, d, J=1.9 Hz), 7.13-7.73(12H, m), 8.33(1H, d, J=8.6 Hz), 8.47(1H, d, J= 3.8 Hz), 9.17(1H,brs).

TABLE 31 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-66

1.23(6H, t, J=7.2 Hz), 2.88 (3H, s), 2.97(3H, s), 3.61 (2H, s), 4.23(4H,q, J=7.2 Hz), 4.85(2H, s), 7.03(1H, d, J=7.1 Hz), 7.23-7.68 (12H, m),7.74(1H, dd, J= 1.1 Hz, J=7.5 Hz). 7.84(1H, brs). 2-67

1.23(6H, t, J=7.2 Hz), 2.88 (3H, s), 2.96(3H, s), 3.62 (2H, s), 4.23(4H,q, J=7.2 Hz), 4.85(2H, s), 7.09(1H, d, J=7.5 Hz), 7.24-7.68 (12H, m),7.74-7.80(2H, m). 2-68

1.22(6H, t, J=7.2 Hz), 2.26 (3H, s), 2.84(3H, brs), 2.95 (3H, brs),3.48(2H, s), 4.10-4.61(4H, m), 4.88 (2H, s), 6.99-7.73(14H, m), 8.43(1H,d, J=8.3 Hz), 9.18(1H, brs). 2-69

1.21(6H, t, J=7.2 Hz), 2.32 (3H, s), 2.81(3H, brs), 2.93 (3H, brs),3.51(2H, s), 4.20(4H, q, J=7.2 Hz), 4.81 (2H, s), 7.01-7.74(14H, m),8.36(1H, d, J=8.3 Hz), 9.19(1H, br-s). 2-70

1.21(6H, t, J=7.2 Hz), 2.33 (3H, s), 2.82(3H, brs), 2.94 (3H, brs),3.51(2H, s), 4.20(4H, q, J=7.2 Hz), 4.81 (2H, s), 7.01-7.74(14H, m),8.35(1H, d, J=8.3 Hz), 9.19(1H, brs).

TABLE 32 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-71

1.24(6H, t, J=7.2 Hz), 2.84 (3H, br-s), 2.95(3H, brs), 3.44(2H, s),4.12-4.35(4H, m), 4.94(2H, s), 7.00(1H, d, J=2.2 Hz), 7.05-7.73 (13H,m), 8.31(1H, d, J= 8.3 Hz), 9.19(1H, brs). 2-72

1.22(6H, t, J=7.1 Hz), 2.81 (3H, brs), 2.94(3H, brs), 3.51(2H, s),4.21(4H, q, J=7.1 Hz), 4.80(2H, s), 7.03(1H, d, J=2.2 Hz),7.14-7.64(12H, m), 7.70 (1H, dd, J=1.6 Hz, J=7.2 Hz), 8.36(1H, d, J=8.6Hz), 9.19(1H, brs). 2-73

1.21(6H, t, J=7.2 Hz), 2.80 (3H, brs), 2.94(3H, brs), 3.50(2H, s),4.20(4H, q, J=7.2 Hz), 4.80(2H, s), 7.02(1H, d, J=2.3 Hz),7.18-7.71(13H, m), 8.36 (1H, d, J=8.3 Hz), 9.18(1H, brs). 2-74

1.16(3H, t, J=7.0 Hz), 1.18 (3H, t, J=7.2 Hz), 2.82 (3H, brs), 2.93(3H,brs), 3.04(1H, d, J=16.5 Hz), 3.20(H, d, J=16.5 Hz), 3.46 (2H, s),4.04-4.20(4H, m), 4.75(1H, d, J=11.4 Hz), 4.82(1H, d, J=11.4 Hz),6.98(1H, d, J=2.2 Hz), 7.11-7.72(4H, m), 8.34 (1H, d, J=8.8 Hz), 9.17(1H, brs). 2-75

1.22(6H, t, J=7.1 Hz), 2.84 (3H, brs), 2.94(3H, brs), 3.44(2H, s),3.74(3H, s), 4.22(4H, q, J=7.1 Hz), 4.81 (2H, s), 6.84-7.71(14H, m),8.32(1H, d, J=8.7 Hz), 9.18(1H, brs).

TABLE 33 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-76

1.21(6H, t, J=7.1 Hz), 2.82 (3H, brs), 2.94(3H, brs), 3.51(2H, s),3.77(3H, s), 4.20(4H, q, J=7.1 Hz), 4.81 (2H, s), 6.83-6.91(3H, m),7.04(1H, d, J=1.9 Hz), 7.18-7.71(10H, m), 8.35 (1H, d, J=8.3 Hz), 9.19(1H, brs). 2-77

1.21(6H, t, J=7.1 Hz), 2.80 (3H, brs), 2.93(3H, brs), 3.51(2H, s),3.79(3H, s), 4.20(4H, q, J=7.1 Hz), 4.80 (2H, s), 6.84(2H, dt, J=8.6 Hz,J=3.4 Hz), 7.03(1H, d, J=1.9 Hz), 7.19-7.71 (11H, m), 8.36(1H, d, J= 8.7Hz), 9.18(1H, brs). 2-78

1.21(6H, t, J=7.2 Hz), 2.82 (3H, brs), 2.94(3H, brs), 3.52(2H, s),4.21(4H, q, J=7.2 Hz), 4.83(2H, s), 7.05(1H, s), 7.19-7.30(6H, m),7.61-7.84(7H, m), 8.34 (1H, d, J=8.3 Hz), 9.40 (1H, brs) 2-79

1.20(6H, t, J=7.2 Hz), 2.86 (3H, brs), 3.06(3H, brs), 3.50(2H, s),4.20(4H, q, J=7.2 Hz), 4.82(2H, s), 7.06(1H, s), 7.15(1H, dd, J=2.1, 8.3Hz), 7.28-7.63 (12H, m), 8.14(1H, d, J= 8.3 Hz), 9.25(1H, brs) 2-80

1.21(6H, t, J=7.0 Hz), 2.83 (3H, brs), 3.00(3H, brs), 3.51(2H, s),4.21(4H, q, J=7.0 Hz), 4.82(2H, s), 7.05(1H, d, J=2.2 Hz), 7.19 (1H, dd,J=2.2, 8.4 Hz), 7.25-7.65(12H, m), 8.27 (1H, d, J=8.4 Hz), 9.28 (1H,brs)

TABLE 34 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-81

1.24(6H, t, J=7.2 Hz), 2.44 (3H, s), 2.61(3H, t, J=7.1 Hz), 2.86(3H,brs), 2.95 (3H, brs), 3.46(2H, s), 4.07 (2H, t, J=7.1 Hz), 4.23(4H, q,J=7.2 Hz), 4.82(2H, s), 7.07-7.63(14H, m), 8.37 (1H, d, J=8.7 Hz), 9.12(1H, brs) 2-82

1.21(6H, t, J=7.1 Hz), 1.45 (3H, t, J=7.2 Hz), 2.81(3H, brs), 2.95(3H,brs), 3.50 (2H, s), 4.11(2H, q, J=7.2 Hz), 4.21(4H, q, J=7.1 Hz),4.82(2H, s), 6.86(1H, d, J= 2.6 Hz), 6.97(1H, dd, J= 2.6, 8.7 Hz),7.03(1H, d, J= 1.9 Hz), 7.18(1H, dd, J= 1.9, 8.7 Hz), 7.28-7.30(5H, m),7.56-7.67(5H, m), 8.36 (1H, d, J=8.7 Hz), 9.17(1H, brs) 2-83

1.21(6H, t, J=7.2 Hz), 1.28 (6H, d, J=6.0 Hz), 2.81(3H, brs), 2.95(3H,brs), 4.21 (4H, q, J=7.2 Hz), 4.64(1H, sept, J=6.0 Hz), 4.82(2H, s),6.85(1H, d, J=2.2 Hz), 6.96(1H, dd, J=2.6, 8.7 Hz), 7.03(1H, d, J=2.2Hz), 7.18(1H, dd, J=8.7, 1.9 Hz), 7.28-7.30(5H, m), 7.56-7.66(5H, m),8.36 (1H, d, J=8.3 Hz), 9.16 (1H, brs) 2-84

1.24(6H, t, J=7.2 Hz), 2.61 (2H, t, J=7.1 Hz), 2.89(3H, brs), 2.94(3H,brs), 3.47 (2H, s), 4.08(2H, t, J=7.1 Hz), 4.24(4H, q, J=7.2 Hz),7.11-7.39(7H, m), 7.61- 7.83(7H, m), 8.34(1H, d, J=8.7 Hz), 9.36(1H,brs) 2-85

1.20(6H, t, J=7.2 Hz), 2.81 (3H, brs), 3.02(3H, brs), 3.49(2H, s),3.78(3H, s), 4.20(4H, q, J=7.2 Hz), 4.81 (2H, s), 7.02(1H, d, J=1.9 Hz),7.07(1H, d, J=8.3 Hz), 7.15(1H, dd, J=2.3, 8.7 Hz), 7.24-7.30(6H, m),7.41-7.60(5H, m), 8.22 (1H, d, J=8.7 Hz), 9.05 (1H, brs)

TABLE 35 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-86

1.21(6H, t, J=7.2 Hz), 2.48 (3H, s), 2.69(3H, brs), 2.91 (3H, brs),3.50(2H, s), 4.21 (4H, q, J=7.2 Hz), 4.82 (2H, s), 6.99(1H, d, J=2.2Hz), 7.20(1H, dd, J=1.5, 8.3 Hz), 7.28-7.41(8H, m), 7.57-7.64(4H, m),8.18 (1H, d, J=8.6 Hz), 8.81 (1H, brs) 2-87

1.23(6H, t, J=7.2 Hz), 3.00 (3H, brs), 3.03(3H, brs), 3.58(2H, s),4.22(4H, q, J= 7.2 Hz), 4.85(2H, s), 7.18 (1H, d, J=1.9 Hz), 7.28-7.33(6H, m), 7.79(1H, d, J=7.9 Hz), 7.92(1H, d, J= 7.9 Hz), 7.99(1H, s),8.35 (1H, d, J=8.3 Hz), 9.46 (1H, s) 2-88

1.21(6H, t, J=7.2 Hz), 2.33 (3H, s), 2.76(3H, brs), 2.93 (3H, brs),3.50(2H, s), 4.21 (4H, q, J=7.2 Hz), 4.82 (2H, s), 6.99(1H, d, J=1.2Hz), 7.14-7.51(13H, m), 7.65(1H, d, J=7.6 Hz), 8.34 (1H, d, J=8.6 Hz),8.78 (1H, brs) 2-89

1.24(6H, t, J=7.2 Hz), 1.29 (3H, t, J=7.6 Hz), 2.92(2H, q, J=7.6 Hz),3.03(6H, brs), 3.57(2H, s), 4.23(4H, q, J=7.2 Hz), 4.85(2H, s), 7.18(1H,d, J=2.3 Hz), 7.27-7.33(6H, m), 7.51-7.60(3H, m), 8.40 (1H, d, J=8.2Hz), 9.51 (1H, brs) 2-90

1.21(6H, t, J=7.1 Hz), 1.22 (3H, t, J=6.9 Hz), 2.64(H, q, J=6.9 Hz),2.75(3H, brs), 2.93(3H, brs), 3.50(2H, s), 4.21(4H, q, J=7.1 Hz), 4.82(2H, s), 6.99(1H, d, J=1.8 Hz), 7.17-7.66(14H, m), 8.30(1H, d, J=8.3Hz), 8.76 (1H, brs)

TABLE 36 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-91

1.21(6H, t, J=7.1 Hz), 2.13 (3H, s), 2.71(3H, brs), 2.89 (3H, brs),3.49(2H, s), 4.20 (4H, q, J=7.1 Hz), 4.82 (2H, s), 5.10(1H, s), 5.43(1H, s), 6.98(1H, d, J=2.2 Hz), 7.19(1H, dd, J=1.9, 8.3 Hz),7.28-7.53(12H, m), 7.67(1H, d, J=7.6 Hz), 8.39(1H, d, J=8.6 Hz), 8.87(1H, brs) 2-92

1.21(6H, t, J=7.1 Hz), 1.21 (6H, t, J=7.1 Hz), 2.76(3H, brs), 2.89(1H,sept, J=7.1 Hz), 2.94(3H, brs), 3.50 (2H, s), 4.21(4H, q, J=7.1 Hz),4.82(2H, s), 7.01(1H, d, J=1.9 Hz), 7.14-7.51 (13H, m), 7.62(1H, d, J=6.4 Hz), 8.21(1H, d, J=8.3 Hz), 8.70(1H, brs) 2-93

1.23(6H, t, J=7.2 Hz), 2.12 (3H, s), 2.99(3H, brs), 3.04 (3H, brs),3.56(2H, s), 4.23 (4H, q, J=7.2 Hz), 4.85 (2H, s), 5.15(1H, s), 5.23(1H, s), 7.15(1H, d, J=1.8 Hz), 7.25-7.31(6H, m), 7.55(1H, s), 7.61(1H,d, J= 7.9 Hz), 7.73(1H, d, J=7.9 Hz), 8.36(1H, d, J=8.3 Hz), 9.35(1H, m)2-94

1.24(6H, t, J=7.2 Hz), 1.29 (6H, t, J=6.8 Hz), 3.03(6H, brs), 3.44(1H,sept, J=6.8 Hz), 3.57(2H, s), 4.23 (4H, q, J=7.2 Hz), 4.85 (2H, s),7.18(1H, d, J=1.9 Hz), 7.26-7.33(6H, m), 7.52(2H, s), 7.63(1H, s),8.41(1H, d, J=8.3 Hz), 9.44 (1H, brs) 2-95

1.23(6H, t, J=7.1 Hz), 3.01 (3H, brs), 3.10(3H, brs), 3.57 (2H, s),4.23(4H, q, J= 7.1 Hz), 4.85(2H, s), 6.91- 6.96(1H, m), 7.20-7.41 (12H,m), 7.46(1H, s), 7.66 (1H, d, J=7.7 Hz), 8.29 (1H, d, J=8.3 Hz), 9.78(1H, s), 10.17(1H, brs)

TABLE 37 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-96 

1.21(6H, t, J=7.1 Hz), 2.75 (3H, brs), 3.02(3H, brs), 3.55(2H, s),4.20(4H, q, J= 7.1 Hz), 4.84(2H, s), 6.92 (1H, d, J=8.3 Hz), 7.15-7.68(14H, m), 8.07(1H, dd, J=1.3, 7.7 Hz) 2-97 

1.22(6H, t, J=7.1 Hz), 2.83 (3H, brs), 2.86(3H, brs), 3.53(2H, s),4.21(4H, q, J= 7.1 Hz), 4.83(2H, s), 6.85 (1H, d, J=7.7 Hz), 7.07 (1H,d, J=2.0 Hz), 7.20- 7.52(12H, m), 8.25(1H, dd, J=1.8, 7.9 Hz), 8.41(1H,d, J=8.5 Hz), 10.48(1H, brs) 2-98 

0.65(6H, t, J=7.4 Hz), 1.69 (4H, q, J=7.4 Hz), 2.81 (3H, brs), 2.94(3H,brs), 3.50(2H, s), 4.30(2H, s), 7.02(1H, d, J=1.8 Hz), 7.18-7.62(13H,m), 7.70 (1H, d, J=7.3 Hz), 8.35(1H, d, J=8.5 Hz), 9.15(1H, brs) 2-99 

1.21(6H, t, J=7.1 Hz), 2.87 (6H, brs), 3.53(2H, s), 4.21 (4H, q, J=7.1Hz), 4.83 (2H, s), 6.92(1H, d, J=7.6 Hz), 7.08(1H, d, J=2.1 Hz),7.20-7.48(10H, m), 7.63 (2H, d, J=8.7 Hz), 8.23 (1H, dd, J=1.7, 7.9 Hz),8.35(1H, d, J=8.5 Hz), 10.38(1H, brs) 2-100

0.85-0.93(4H, m), 2.78 (3H, brs), 2.93(3H, brs), 3.52(2H, s), 4.16(2H,s), 7.04(1H, d, J=2.1 Hz), 7.17-7.61(13H, m), 7.70 (1H, dd, J=1.5, 7.2Hz), 8.35(1H, d, J=9.0 Hz), 9.15 (1H, brs)

TABLE 38 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-101

2.79(3H, brs), 2.94(3H, brs), 3.45(2H, s), 4.31(1H, t, J=7.6 Hz),4.62(2H, d, J=7.6 Hz), 6.96(1H, d, J=2.0 Hz), 7.15-7.69 (19H, m),8.30(1H, d, J= 8.5 Hz), 9.15(1H, brs) 2-102

1.62-1.76(4H, m), 1.82-1.99(4H, m), 2.78 (3H, brs), 2.93(3H, brs),3.44(2H, s), 4.08(2H, s), 6.97(1H, d, J=2.0 Hz), 7.09-7.26(6H, m), 7.35-7.72(8H, m), 8.34(1H, d, J=8.5 Hz), 9.15(1H, brs) 2-103

2.40(1H, t, J=5.7 Hz), 2.42(1H, t, J=6.3 Hz), 3.53 (2H, s), 2.80(3H,brs), 2.93(3H, brs), 3.82(2H, dd, J=6.3, 11.4 Hz), 3.96 (2H, dd, J=5.7,11.4 Hz), 4.58(2H, s), 7.01(1H, d, J=1.8 Hz), 7.14-7.71(14H, m),8.29(1H, d, J=8.4 Hz), 9.05(1H, brs) 2-104

1.98(6H, s), 2.83(3H, brs), 2.93(3H, brs), 3.49(2H, s), 4.40(4H, s),4.44(2H, s), 7.00(1H, d, J=2.2 Hz), 7.15 (1H, dd, J=2.2, 8.4 Hz),7.22-7.65(12H, m), 7.70 (1H, dd, J=1.9, 7.0 Hz), 8.32(1H, d, J=8.4 Hz),9.13 (1H, brs) 2-105

1.23(6H, t, J=7.1 Hz), 2.83(3H, brs), 2.94(3H, brs), 3.51(2H, s),4.22(4H, q, J=7.1 Hz), 4.82(2H, s), 6.94-7.04(3H, m), 7.16-7.71(10H, m),8.34 (1H, d, J=8.5 Hz), 9.17 (1H, brs)

TABLE 39 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-106

1.22(6H, t, J=7.1 Hz), 2.81 (3H, brs), 2.93(3H, brs), 3.50(2H, s),4.20(4H, q, J= 7.1 Hz), 4.79(2H, s), 7.01- 7.04(2H, m), 7.25-7.71 (11H,m), 8.35(1H, d, J= 8.5 Hz), 9.17(1H, brs) 2-107

1.25(6H, t, J=7.1 Hz), 2.75 (3H, brs), 2.92(3H, brs), 3.78(2H, s),4.22(4H, q, J= 7.1 Hz), 4.85(2H, s), 6.98 (1H, s), 7.28-7.72(13H, m),8.71(1H, s), 9.52(1H, brs) 2-108

1.22(6H, t, J=7.2 Hz), 2.13 (3H, s), 2.85(3H, brs), 2.93 (3H, brs),3.50(2H, s), 4.16-4.26(4H, m), 4.80 (2H, s), 6.78(1H, d, J=5.1 Hz),7.05(1H, d, J=2.2 Hz), 7.15(1H, d, J=5.2 Hz), 7.16-7.64(8H, m), 7.69(1H, d, J=1.5, 7.3 Hz), 8.33 (1H, d, J=8.5 Hz), 9.16 (1H, brs) 2-109

1.22(6H, t, J=7.2 Hz), 2.44 (3H, s), 2.84(3H, brs), 2.94 (3H, brs),3.52(2H, s), 4.20(4H, q, J=7.2 Hz), 4.78 (2H, s), 6.58(1H, dd, J= 1.2,3.5 Hz), 6.76(1H, d, J=3.5 Hz), 7.04(1H, d, J=2.0 Hz), 7.20(1H, dd,J=2.1, 8.6 Hz), 7.37- 7.62(7H, m), 7.68(1H, dd, J=1.4, 7.6 Hz), 8.33(1H,d, J=8.4 Hz), 9.17(1H, brs) 2-110

1.22(6H, t, J=7.1 Hz), 2.85 (3H, brs), 2.94(3H, brs), 3.46(2H, s),4.23(4H, q, J= 7.1 Hz), 4.97(2H, s), 7.00 (1H, d, J=2.2 Hz), 7.13-7.16(1H, m), 7.36(1H, d, J=3.3 Hz), 7.38-7.71(8H, m), 7.75(1H, d, J=3.3Hz), 8.31(1H, d, J=8.5 Hz), 9.16 (1H, brs)

TABLE 40 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-111

0.97(6H, d, J=7.2 Hz), 1.21 (6H, t, J=7.2 Hz), 2.45(1H, sep. J=7.2 Hz),2.88(3H, brs), 2.94(2H, brs), 3.52 (2H, s), 4.15(4H, q, J= 7.2 Hz),4.50(2H, s), 7.09 (1H, d, J=2.3 Hz), 7.20- 7.72(9H, m), 8.34(1H, d,J=8.3 Hz), 9.15(1H, brs). 2-112

0.90(3H, t, J=7.2 Hz), 0.92 (3H, t, J=6.5 Hz), 0.95- 1.10(1H, m),1.21(3H, t, J= 7.2 Hz), 1.48-1.62(1H, m), 2.05-2.16(1H, m), 2.88 (3H,brs), 2.94(3H, brs), 3.52(2H, s), 4.14(4H, q, J= 7.2 Hz), 4.51(2H, s),7.09 (1H, d, J=1.9 Hz), 7.21- 7.72(9H, m), 8.36(1H, d, J=8.3 Hz),9.16(1H, brs). 2-113

0.83(6H, d, J=6.4 Hz), 1.21 (6H, t, J=7.2 Hz), 1.51- 1.65(1H, m),1.88(2H, d, J= 6.4 Hz), 2.88(3H, brs), 2.94 (3H, brs), 3.53(2H, s), 4.15(4H, q, J=7.2 Hz), 4.52(2H, s), 7.08(1H, d, J=2.3 Hz), 7.22-7.71(9H, m),8.37(1H, d, J=8.3 Hz), 9.16 (1H, brs). 2-114

0.88(3H, t, J=7.2 Hz), 1.09-1.31(2H, m), 1.21 (6H, t, J=7.2 Hz), 1.79-1.93(2H, m), 2.89(3H, brs), 2.94(3H, brs), 3.53(2H, s), 4.15(4H, q,J=7.2 Hz), 4.49(2H, s), 7.09(1H, brs), 7.21-7.74(9H, m), 8.37 (1H, d,J=8.3 Hz), 9.15 (1H, brs). 2-115

0.83(3H, t, J=7.5 Hz), 1.21 (6H, t, J=7.2 Hz), 1.96(2H, q, J=7.5 Hz),2.88(3H, brs), 2.94(3H, brs), 3.53 (2H, s), 4.16(4H, q, J= 7.2 Hz),4.50(2H, s), 7.08 (1H, d, J=1.9 Hz), 7.21- 7.74(9H, m), 8.36(1H, d,J=8.7 Hz), 9.15(1H, brs).

TABLE 41 Example Structure NMR (δ, 300 MHz, CDCl₃) 2-116

0.86(3H, t, J=7.2 Hz), 1.06-1.36(4H, m), 1.21 (6H, t, J=7.2 Hz), 1.84-1.94(2H, m), 2.88(3H, brs), 2.94(3H, brs), 3.53(2H, s), 4.15(4H, q,J=7.2 Hz), 4.49 (2H, s), 7.08(1H, d, J=2.3 Hz), 7.21-7.71(9H, m),8.37(1H, d, J=8.6 Hz), 9.16(1H, brs). 2-117

1.21(6H, t, J=7.1 Hz), 2.67(2H, d, J=7.4 Hz), 2.87 (3H, brs), 2.95(3H,brs), 3.54(2H, s), 4.10-4.20(4H, m), 4.47(2H, s), 5.00- 5.10(2H, m),5.56-5.67 (1H, m), 7.09(1H, d, J= 2.1 Hz), 7.24(1H, d, J=2.0 Hz),7.38-7.68(7H, m), 7.70(1H, d, J=1.4 Hz), 8.37(1H, d, J=8.4 Hz), 9.14(1H,brs) 2-118

1.25(9H, t, J=7.2 Hz), 2.89(3H, brs), 2.95(3H, brs), 3.56(2H, s),4.23(6H, q, J=7.2 Hz), 4.70(2H, s), 7.11(1H, d, J=1.8 Hz), 7.24(1H, d,J=2.2 Hz), 7.28-7.70(8H, m), 8.36 (1H, d, J=8.8 Hz), 9.16 (1H, brs)2-119

0.87(3H, t, J=7.2 Hz), 0.92(3H, t, J=6.8 Hz), 1.00-1.16(2H, m), 1.20(6H, t, J=7.1 Hz), 1.38- 1.53(2H, m), 2.18-2.23 (1H, m), 2.88(3H, brs),2.95(3H, brs), 3.52(2H, s), 4.08-4.18(4H, m), 4.50(2H, d, J=2.1 Hz),7.08(1H, d, J=1.9 Hz), 7.22-7.69(9H, m), 8.35 (1H, d, J=8.6 Hz), 9.15(1H, brs)

Example 32-(2-{3-Ethoxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester a) 3-Ethoxy-4-nitrobenzoic acid methyl ester

To a suspension of sodium hydride (60% mineral oil: 1.20 g) indimethylformamide (50 mL) was added 3-hydroxy-4-nitrobenzoic acid methylester (4.93 g) under ice-cooling, and the mixture was stirred at roomtemperature for 30 minutes. After addition of ethyl iodide (4.4 g), thesolution was stirred at 60° C. overnight, cooled down to roomtemperature, poured into saturated aqueous ammonium chloride, andextracted with ethyl acetate-tetrahydrofuran. The organic layer waswashed with saturated aqueous ammonium chloride and saturated brine,dried over sodium sulfate and concentrated to give a solid, which waswashed with ethyl acetate-hexane to afford 3-ethoxy-4-nitrobenzoic acidmethyl ester (3.30 g) as a pale yellow solid.

b) 3-Ethoxy-4-nitrobenzoic acid chloride

3-Ethoxy-4-nitrobenzoic acid chloride was obtained in a similar mannerto Example 1f) and Example 1d) from the 3-ethoxy-4-nitrobenzoic acidmethyl ester obtained in Example 3a).

c) 2′-Diazo-3-ethoxy-4-nitroacetophenone

A solution of the 3-ethoxy-4-nitrobenzoic acid chloride (2.06 g)obtained in Example 3b) in diethyl ether (30 mL) was added dropwise to amixture of diazomethane in diethyl ether (0.35M, 64 mL) andtriethylamine (3.12 mL) under ice-cooling. The mixture was stirred for 2hours under ice-cooling and the temperature was raised to roomtemperature, followed by stirring overnight. After addition of aceticacid (1 mL), the mixture was stirred at room temperature for one hourand evaporated to remove the solvent. The residue was purified by columnchromatography on silica gel with hexane:ethyl acetate=5:2 to give thetitle compound (1.80 g) as a yellow solid.

d) 3-Ethoxy-4-nitrophenylacetic acid ethyl ester

A solution of silver benzoate (270 mg) in triethylamine (2.7 ml) wasadded dropwise in 10 divided doses to a solution of the2′-diazo-3-ethoxy-4-nitroacetophenone (1.80 g) obtained in Example 3c)in ethanol (25 mL) under ref lux. The mixture was ref luxed for 9 hoursand the reaction solution was filtered through a Celite pad. Thefiltrate was concentrated, and the concentrate was diluted with diethylether and washed with 10% aqueous sodium carbonate, water and saturatedbrine. The organic layer was dried over sodium sulfate and purified bycolumn chromatography on silica gel with hexane:ethyl acetate=4:1 togive the title compound (1.27 g) as a yellow solid.

e) 4-Amino-3-ethoxyphenylacetic acid ethyl ester

The 3-ethoxy-4-nitrophenyl-acetic acid ethyl ester (1.27 g) obtained inExample 3d) was subjected to reactions similar to those in Example 1-3d)to give the title compound (1.12 g) as a brown oil.

f)2-(2-{3-Ethoxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester

The 4-amino-3-ethoxyphenylacetic acid ethyl ester obtained in Example3e) and the 2-hydroxymethyl-2-phenylmalonic acid diethyl ester obtainedin Example 1-2a) were subjected to reactions similar to those inExamples 1e), 1f) and 1 g) to give the title compound (0.159 g) (seeTable 42).

Example 3-2{3-Hydroxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester

{3-Benzyloxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester (300 mg) obtained in asimilar manner to Example 3, except that reduction of the nitro groupwas carried out with iron dust, was subjected to reactions in a similarmanner to Example 1-2c) to give the title compound (244 mg) (See Table42).

Examples 3-3 to 3-16

Compounds of Examples 3-3 to 3-16 were obtained in a similar manner toExamples 3 to 3-2. The compounds thus obtained were shown in Tables 42to 45.

TABLE 42 Example Structure NMR (δ, 300 MHz, CDCl₃) 3

1.19(6H, t, J=7.1 Hz), 1.20(3H, t, J=7.1 Hz), 3.49(2H, s), 3.77(2H, q,J=7.1 Hz), 4.18(4H, q, J=7.1 Hz), 4.83(2H, s), 6.59(1H, d, J=1.5 Hz),6.75(1H, dd, J=1.5, 8.2 Hz), 7.25-7.33(5H, m), 7.44(1H, dd, J=1.5, 7.2Hz), 7.49-7.66(6H, m), 7.70-7.76(1H, m), 7.80 (1H, dd, J=1.5, 7.2 Hz),8.35(1H, d, J=8.0 Hz) 3-2

1.05(6H, t, J=7.2 Hz), 3.23 (4H, dq, J=7.2, 7.2 Hz), 3.48(2H, s),4.83(2H, s), 6.48(1H, d, J=7.9 Hz), 6.55(1H, dd, J=7.9, 1.9 Hz),6.77(1H, d, J=1.5 Hz), 7.17-7.86(15H, m), 8.58(1H, s) 3-3

1.05(6H, t, J=7.2 Hz), 3.23 (4H, dq, J=7.2, 7.2 Hz), 3.53(2H, s),3.55(3H, s), 4.83(2H, s), 6.60(1H, s), 6.73(1H, d, J=7.9 Hz),7.10-7.66(15H, m), 7.85(1H, dd, J=7.5, 1.5 Hz), 8.33(1H, d, J=7.9 Hz)3-4

1.19(6H, t, J=6.9 Hz), 3.50 (5H, s), 4.17(4H, q, J=6.9 Hz), 4.83(2H, s),6.58(1H, s), 6.75(1H, d, J=6.9 Hz), 7.26-7.65(13H, m), 7.85(1H, d, J=7.3Hz), 8.31(1H, d, J=8.1 Hz) 3-5

0.84(6H, t, J=7.2 Hz), 1.43(4H, tq, J=7.2, 7.2 Hz), 3.16(4H, m),3.52(2H, s), 3.55(3H, s), 4.83(2H, s), 6.60(1H, br.s), 6.72(1H, dd,J=8.3, 1.5 Hz), 7.12- 7.66(15H, m), 7.84(1H, dd, J=7.9, 1.9 Hz),8.33(1H, d, J=7.9 Hz)

TABLE 43 Example Structure NMR (δ, 300 MHz, CDCl₃) 3-6 

1.13(6H, t, J=7.2 Hz), 2.55 (2H, t, J=8.0 Hz), 3.30(4H, dq, J=7.2, 7.2Hz), 3.53 (2H, s), 3.57(3H, s), 4.12 (2H, t, J=8.0 Hz), 6.67(1H, br.s),6.82(1H, dd, J=8.3, 1.9 Hz), 7.26-7.66(15H, m), 7.84(1H, dd, J=7.9, 1.9Hz), 8.33(1H, d, J=7.9 Hz) 3-7 

1.05(6H, t, J=7.2 Hz), 1.24 (3H, t, J=7.1 Hz), 3.17- 3.29(4H, m),3.52(2H, s), 3.83(2H, q, J=7.1 Hz), 4.82 (2H, s), 6.60(1H, d, J=1.5 Hz),6.69-6.76(1H, m), 7.04-7.14(2H, m), 7.15- 7.22(2H, m), 7.25-7.34 (3H,m), 7.41-7.47(1H, m), 7.49-7.66(6H, m), 7.73 (1H, br-s), 7.77-7.83(1H,m), 8.37(1H, d, J=8.3 Hz) 3-8 

1.13(6H, t, J=7.2 Hz), 1.24 (3H, t, J=7.1 hz), 2.49- 2.59(2H, m),3.31(4H, dq, J=5.3, 7.2 Hz), 3.52(2H, s), 3.87(2H, q, J=7.1 Hz),4.07-4.17(2H, m), 6.68 (1H, d, J=1.5 Hz), 6.78- 6.84(1H, m), 7.23-7.37(5H, m), 7.41-7.47(1H, m), 7.48-7.66(8H, m), 7.73 (1H, s), 7.76-7.82(1H,m), 8.37(1H, d, J=8.3 Hz) 3-9 

1.10(6H, d, J=6.0 Hz), 1.19 (6H, t, J=7.2 Hz), 3.48(2H, s), 4.19(4H, q,J=7.2 Hz), 4.36(1H, sept, J=6.0 Hz), 4.82(2H, s), 6.62(1H, d, J= 1.5Hz), 6.70-6.77(1H, m), 7.27-7.32(5H, m), 7.41- 7.46(1H, m), 7.49-7.67(6H, m), 7.72-7.82(2H, m), 8.39(1H, d, J=8.2 Hz) 3-10

1.05(6H, t, J=7.2 Hz), 1.13 (6H, d, J=6.1 Hz), 3.23(4H, dq, J=5.6, 7.2Hz), 3.52 (2H, s), 4.40(1H, sept, J= 6.1 Hz), 4.82(2H, s), 6.62 (1H, d,J=1.5 Hz), 6.67- 6.75(1H, m), 7.10(2H, br-t, J=5.6 Hz), 7.16-7.23(2H,m), 7.24-7.35(3H, m), 7.44 (1H, dd, J=1.5, 7.6 Hz), 7.50-7.70(6H, m),7.71- 7.82(2H, m), 8.40(1H, d, J=8.3 Hz)

TABLE 44 Example Structure NMR (δ, 300 MHz, CDCl₃) 3-11

1.13(6H, t, J=7.2 Hz), 1.13 (6H, d, J=6.1 Hz), 2.48- 2.60(2H, m),3.31(4H, dq, J=5.7, 7.2 Hz), 3.52(2H, s), 4.07-4.17(2H, m), 4.43 (1H,sept, J=6.1 Hz), 6.69 (1H, d, J=1.5 Hz), 6.79 (1H, dd, J=1.5, 8.3 Hz),7.23-7.37(5H, m), 7.41- 7.46(1H, m), 7.48-7.68 (8H, m), 7.72-7.82(2H,m), 8.40(1H, d, J=8.3 Hz) 3-12

0.90(3H, t, J=7.4 Hz), 1.05 (6H, t, J=7.3 Hz), 1.53- 1.69(2H, m),3.16-3.30 (4H, m), 3.53(2H, s), 3.75 (2H, t, J=6.7 Hz), 4.82(2H, s),6.58-6.74(2H, m), 7.02-7.78(16H, m), 8.36 (1H, d, J=8.2 Hz) 3-13

1.04(6H, t, J=7.2 Hz), 3.23 (4H, dq, J=7.2, 7.2 Hz), 3.52(2H, s),4.82-4.86(4H, m), 6.70-7.79(16H, m), 7.71(1H, br.s), 7.78(1H, dd, J=7.1,1.9 Hz), 8.40 (1H, d, J=8.3 Hz) 3-14

1.19(6H, t, J=7.1 Hz), 3.49 (2H, s), 4.17(4H, q, J=7.1 Hz), 4.78(2H, s),4.83(2H, s), 6.70(1H, d, J=1.9 Hz), 6.78(1H, dd, J=8.3, 1.5 Hz),7.21-7.57(12H, m), 7.70(1H, br.s), 7.77(1H, dd, J=7.2, 1.9 Hz), 8.38(1H, d, J=8.3 Hz) 3-15

1.20(6H, t, J=7.2 Hz), 3.47 (2H, s), 4.19(4H, q, J=7.2 Hz), 4.82(2H, s),6.29(1H, d, J=7.9 Hz), 6.57(1H, dd, J=7.9, 1.9 Hz), 6.79(1H, d, J=1.9Hz), 7.18(1H, br.s) 7.28-7.74(11H, m), 7.86 (1H, dd, J=7.9, 1.5 Hz),8.39(1H, s)

TABLE 45 Example Structure NMR (δ, 300 MHz, CDCl₃) 3-16

1.17(6H, t, J=7.1 Hz), 3.54(2H, s), 3.72(3H, s), 4.16(4H, q, J=7.1 Hz),4.83(2H, s), 6.72-6.80(3H, m), 7.29-7.66(12H, m), 8.14(1H, dd, J=1.3,7.7 Hz)

Example 42-{3-Dimethylamino-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester a)2-(3-Bromo-4-nitrophenyl)malonic acid tert-butyl ester methyl ester

Sodium hydride (60%, mineral oil; 0.985 g) was suspended indimethylformamide (20 mL), and a solution of tert-butyl methyl malonate(4.29 g) in dimethylformamide (5 mL) was added dropwise thereto underice-cooling. After foam generation is stopped, a solution of2-bromo-4-fluoro-1-nitrobenzene (2.71 g) in dimethylformamide (5 mL) wasadded dropwise thereto at the same temperature, and the mixture wasfurther stirred at 60° C. for 3 hours, and then concentrated. Theresidue was neutralized with 1N hydrochloric acid and extracted withethyl acetate. The extract was washed with saturated brine, dried oversodium sulfate and concentrated. The residue was purified by columnchromatography on silica gel with ethyl acetate:hexane=1:4 to 1:5 togive the title compound (7.54 g) as an oil.

b) (3-Bromo-4-nitrophenyl)acetic acid methyl ester

The 2-(3-bromo-4-nitrophenyl)malonic acid tert-butyl ester methyl ester(1.18 g) obtained in Example 4 a) was dissolved in chloroform (10 mL),trifluoroacetic acid (10 g) was added thereto under ice-cooling, and themixture was stirred at room temperature for 5 hours. The reactionmixture was poured gradually into ice and saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over sodium sulfate andconcentrated to give the title compound (0.820 g) as a pale yellow oil.

c) (3-Dimethylamino-4-nitrophenyl)acetic acid methyl ester

The (3-bromo-4-nitrophenyl)acetic acid methyl ester (0.320 g) obtainedin Example 4 b) was dissolved in tetrahydrofuran (10 mL). To thissolution were added triethylamine (0.237 g) and dimethylamine (2Mtetrahydrofuran; 0.58 mL), and stirred overnight while heating. Thereaction mixture was concentrated and purified by column chromatographyon silica gel with ethyl acetate:hexane=1:4 to give the title compound(0.145 g) as an orange oil.

d) (4-Amino-3-dimethylaminophenyl)acetic acid methyl ester

The (3-dimethylamino-4-nitrophenyl)acetic acid methyl ester (0.245 g)obtained in Example 4 c) was subjected to reactions similar to those inExample 1-3 d) to give the title compound (0.188 g) as a red oil.

e)2-{3-Dimethylamino-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester

The (4-amino-3-dimethylaminophenyl)acetic acid methyl ester (0.188 g)obtained in Example 4 d) was subjected to reactions similar to those inExample 1e), 1f) and 1g) to give the title compound (0.058 g) (See Table46).

Examples 4-2 to 4-8

Compounds of Examples 4-2 to 4-8 were obtained in a similar manner toExample 4. The compounds thus obtained were shown in Tables 46 to 47.

TABLE 46 Example Structure NMR (δ, 300 MHz, CDCl₃) 4

1.04(6H, t, J=7.2 Hz), 2.26(6H, s), 3.23(4H, m), 3.51(2H, s), 4.83(2H,s), 6.86-7.80(15H, m), 8.40(1H, d, J=8.7 Hz), 8.45(1H, brs). 4-2

1.05(6H, t, J=7.3 Hz), 1.49(6H, br.s), 2.48(4H, br.s), 3.24(4H, dq,J=7.3, 7.3 Hz), 3.53(2H, s), 4.84(2H, s), 6.93(2H, m), 7.20-7.70(15H,m), 8.40(1H, d, J=9.2 Hz), 8.54(1H, br.s) 4-3

1.04(6H, t, J=7.3 Hz), 1.76(4H, m), 2.59(4H, t, J=6.2 Hz), 3.23(4H, dq,J=7.3, 7.3 Hz), 3.51(2H, s), 4.83(2H, s), 4.82(2H, m), 7.12-7.63(14H,m), 7.74(1H, dd, J=7.3, 1.4 Hz), 8.18(1H, br.s), 8.30(1H, d, J=8.1 Hz)4-4

1.20(6H, t, J=7.1 Hz), 1.48(6H, br.s), 2.47(4H, br.s), 3.49(2H, s),4.19(4H, q, J=7.1 Hz), 4.83(2H, s), 6.92-7.72(15H, m), 8.39(1H, d, J=8.3Hz), 8.56(1H, br.s) 4-5

1.20(6H, t, J=7.2 Hz), 1.74(4H, m), 2.57(4H, m), 3.48(2H, s), 4.19(4H,q, J=7.2 Hz), 4.82(2H, s), 6.90(2H, m), 7.30-7.63(12H, m), 7.74(1H, dd,J=7.2, 1.5 Hz), 8.20(1H, br.s), 8.29(1H, d, J=8.7 Hz)

TABLE 47 Example Structure NMR (δ, 300 MHz, CDCl₃) 4-6

1.20(6H, t, J=7.1 Hz), 2.24(6H, s), 3.48(2H, s), 4.19(4H, q, J=7.1 Hz),4.82(2H, s), 6.88-6.98(2H, m), 7.29(5H, brs), 7.43(1H, d, J=7.2 Hz),7.48-7.60(2H, m), 7.62(4H, s), 7.77(1H, d, J=7.5 Hz), 8.39(1H, d, J=8.3Hz), 8.47(1H, brs). 4-7

1.21(6H, t, J=7.0 Hz), 2.38-2.47(4H, m), 3.51(2H, s), 3.53-3.60(4H, m),4.20(4H, q, J=7.0 Hz), 4.84(2H, s), 6.93(1H, s), 7.00(1H, dd, J=1.5, 7.4Hz), 7.29-7.35(5H, m), 7.47-7.68(7H, m), 7.73(1H, dd, J=1.8, 7.4 Hz),8.42-8.51(2H, m) 4-8

0.67(6H, t, J=7.0 Hz), 1.21(6H, t, J=7.2 Hz), 2.64(4H, q, J=7.0 Hz),3.49(2H, s), 4.21(4H, q, J=7.2 Hz), 4.83(2H, s), 6.90-7.01(2H, m),7.28-7.35(5H, m), 7.42-7.65(7H, m), 7.69(1H, dd, J=1.5, 7.2 Hz),8.41(1H, d, J=8.3 Hz), 8.85(1H, br-s)

Example 52-[2-(2-{2-methyl-3-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxy)ethyl]-2-phenylmalonicacid diethyl ester a) 2′-Diazo-3-nitro-2-methylacetophenone

2-Methyl-3-nitrobenzoic acid (500 mg) was subjected to reactions similarto those in Example 3b) and 3c) to give the title compound (377 mg).

b) 2-Methyl-3-nitrophenylacetic acid ethyl ester

The 2′-diazo-3-nitro-2-methylacetophenone (377 mg) obtained in Example5a) was subjected to reactions similar to those in Example 3d) to givethe title compound (363 mg).

c) 2-Methyl-3-nitrophenylacetic acid

The 2-methyl-3-nitrophenylacetic acid ethyl ester (352 mg) obtained inExample 5b) was subjected to reactions similar to those in Example 1f)to give the title compound (307 mg).

d) 2-(2-Benzyloxyethyl)-2-phenylmalonic acid diethyl ester

Sodium hydride (406 mg) was dissolved in dimethylformamide (20 mL) andthe solution was cooled to 0° C. To this solution was addedphenylmalonic acid diethyl ester (2.0 g), and the mixture was stirred atroom temperature for 30 minutes. Bromoethyl benzyl ether (2.0 g) wasfurther added thereto, stirred at 60° C. for 4 hours, and water wasadded thereto. The reaction mixture was concentrated, diluted with ethylacetate, washed with water, dried over sodium sulfate and purified bycolumn chromatography on silica gel with ethyl acetate:hexane=1:9 togive the title compound (1.2 g).

e) 2-(2-Hydroxyethyl)-2-phenylmalonic acid diethyl ester

The 2-(2-benzyloxyethyl)-2-phenylmalonic acid diethyl ester (1.2 g, notpurified) obtained in Example 5d) was subjected to reactions similar tothose in Example 1-2c) to give the title compound (726 mg).

f) 2-{2-[2-(2-Methyl-3-nitrophenyl)acetoxy]ethyl}-2-phenylmalonic aciddiethyl ester

The 2-methyl-3-nitrophenylacetic acid (307 mg) obtained in Example 5c),4-dimethylaminopyridine (217 mg) and the2-(2-hydroxyethyl)-2-phenylmalonic acid diethyl ester (250 mg) obtainedin Example 5e) were subjected to reactions similar to those in Example1-3c) to give the title compound (366 mg).

g)2-[2-(2-{2-methyl-3-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxy)ethyl]-2-phenylmalonicacid diethyl ester

The 2-{2-[2-(2-methyl-3-nitrophenyl)acetoxy]ethyl}-2-phenylmalonic aciddiethyl ester (345 mg) obtained in Example 5f) was subjected toreactions similar to those in Example 1-3d) and 1-3e) to give the titlecompound (318 mg) (See Table 48).

Examples 5-2 to 5-18

Compounds of Examples 5-2 to 5-18 were obtained in a similar manner toExample 5. The compounds thus obtained were shown in Tables 48 to 51.

TABLE 48 Example Structure NMR (δ, 300 MHz, CDCl₃) 5

1.23(6H, t, J=7.0 Hz), 1.70(3H, s), 2.61(2H, t, J=7.0 Hz), 3.50(2H, s),4.07(2H, t, J=7.0 Hz), 4.21(4H, q, J=7.0 Hz), 6.84(1H, br.s), 6.98(1H,d, J=7.7 Hz), 7.13-7.71(15H, m), 7.80(1H, d, J=7.0 Hz) 5-2

1.17(6H, t, J=7.1 Hz), 3.50(2H, s), 4.14(4H, q, J=7.1 Hz), 4.83(2H, s),6.83(1H, s), 6.91(1H, d, J=7.5 Hz), 6.99(1H, br.s), 7.16-7.81(15H, m)5-3

1.23(6H, t, J=7.2 Hz), 2.62(2H, t, J=7.2 Hz), 3.41(2H, s), 4.13(2H, t,J=7.2 Hz), 4.20(4H, q, J=7.2 Hz), 7.05-7.79(18H, m) 5-4

1.10(6H, t, J=7.2 Hz), 2.53-2.61(2H, m), 3.28 (4H, dq, J=5.3, 7.2 Hz),3.54(2H, s), 4.07-4.17(2H, m), 6.95-7.10(3H, m), 7.14-7.36(7H, m), 7.40-7.46(1H, m), 7.46-7.62 (6H, m), 7.64-7.71(2H, m), 7.77(1H, dd, J=1.5,7.5 Hz) 5-5

0.85(6H, t, J=7.2 Hz), 1.49(4H, tq, J=7.2, 7.2 Hz), 2.54-2.63(2H, m),3.16-3.25(4H, m), 3.53 (2H, s), 4.08-4.17(2H, m), 6.96-7.01(1H, m),7.03-7.10(2H, m), 7.15-7.36(7H, m), 7.40-7.46(1H, m), 7.47-7.62(6H, m),7.65-7.71(2H, m), 7.77 (1H, dd, J=1.5, 7.5 Hz)

TABLE 49 Example Structure NMR (δ, 300 MHz, CDCl₃) 5-6

1.24(6H, t, J=7.4 Hz), 1.68(3H, s), 2.65(2H, t, J=7.3 Hz), 3.50(2H, s),4.09(2H, t, J=7.3 Hz), 4.22(4H, q, J=7.4 Hz), 6.81(1H, br.s),6.92-7.83(16H, m) 5-7

1.23(6H, t, J=7.4 Hz), 2.20(3H, s), 2.63(2H, t, J=7.0 Hz), 3.47(2H, s),4.08(2H, t, J=7.0 Hz), 4.21(4H, q, J=7.4 Hz), 6.94(1H, s),7.07-7.81(16H, m) 5-8

1.11(6H, d, J=6.4 Hz), 1.13(6H, d, J=6.8 Hz), 2.49-2.58(2H, m), 3.53(2H, s), 3.98-4.15(4H, m), 6.96-7.01(1H, m), 7.03-7.16(3H, m),7.17-7.37(8H, m), 7.40-7.61(5H, m), 7.64-7.71(2H, m), 7.77 (1H, dd,J=1.5, 7.6 Hz) 5-9

1.11(6H, t, J=7.0 Hz), 1.72(3H, s), 2.52(2H, t, J=7.9 Hz), 3.29(4H, dq,J=7.0, 7.0 Hz), 3.57(2H, s), 4.08(2H, t, J=7.9 Hz), 6.85(1H, br.s),6.99-7.81(18H, m) 5-10

0.98(6H, t, J=7.1 Hz), 1.53(2H, m), 1.79(3H, s), 1.95(2H, m), 3.09(4H,dq, J=7.1, 7.1 Hz), 3.64(2H, s), 4.06(2H, t, J=5.7 Hz), 7.03-7.62(18H,m), 8.02(1H, br.s)

TABLE 50 Example Structure NMR (δ, 300 MHz, CDCl₃) 5-11

0.86(6H, t, J=7.1 Hz), 1.50(4H, tq, J=7.1, 7.1 Hz), 2.53(2H, t, J=7.9Hz), 3.21(4H, m), 3.57(2H, s), 4.08(2H, t, J=7.9 Hz), 6.85(1H, br.s),7.00(1H, d, J=7.5 Hz), 7.14-7.80(17H, m) 5-12

1.11(6H, t, J=7.2 Hz), 2.53(2H, t, J=7.9 Hz), 3.22(3H, d), 3.29(4H, dq,J=7.2, 7.2 Hz), 3.55(2H, s), 4.09(2H, t, J=7.9 Hz), 6.95(1H, dd, J=7.5,1.5 Hz), 7.04-7.64(16H, m), 7.74(1H, dd, J=7.5, 1.5 Hz), 8.34(1H, dd,J=8.3, 1.1 Hz) 5-13

1.23(6H, t, J=7.1 Hz), 2.61(2H, t, J=7.2 Hz), 3.22(3H, s), 3.49(2H, s),4.08(2H, t, J=7.2 Hz), 4.21(4H, q, J=7.1 Hz), 6.93(1H, dd, J=7.6, 1.5Hz), 7.28-7.75(14H, m), 7.73(1H, dd, J=7.6, 1.5 Hz), 8.33(1H, dd, J=8.3,1.5 Hz) 5-14

1.11(6H, t, J=7.4 Hz), 1.15(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.5 Hz),3.29(6H, m), 3.54(2H, s), 4.09(2H, t, J=7.5 Hz), 6.95(1H, dd, J=7.9, 1.1Hz), 7.10(1H, dd, J=7.9, 7.9 Hz), 7.24-7.73(16H, m), 8.36(1H, d, J=8.3Hz) 5-15

1.15(3H, t, J=7.2 Hz), 1.23(6H, t, J=7.2 Hz), 2.61(2H, t, J=7.2 Hz),3.29(2H, q, J=7.2 Hz), 3.49(2H s), 4.07(2H, t, J=7.2 Hz), 4.21(4H, q,J=7.2 Hz), 6.94(1H, dd, J=7.5, 1.5 Hz), 7.08(1H, dd, J=7.9, 7.9 Hz),7.30- 7.73(14H, m), 8.34(1H, dd, J=7.9, 1.5 Hz)

TABLE 51 Example Structure NMR (δ, 300 MHz, CDCl₃) 5-16

1.05(6H, d, J=6.4 Hz), 1.23(6H, t, J=7.2 Hz), 2.62(2H, t, J=7.2 Hz),3.51(2H, s), 3.85(1H, sep, J=6.4 Hz), 4.10(2H, t, J=7.2 Hz), 4.20(4H, q,J=7.2 Hz), 6.95(1H, dd, J=7.9, 1.5 Hz), 7.07(1H, dd, J=7.9, 7.9 Hz),7.30-7.61(12H, m), 7.68(1H, dd, J=7.9, 1.5 Hz), 7.75(1H, br.s), 8.28(1H,dd, J=7.9, 1.5 Hz) 5-17

1.23(6H, t, J=7.1 Hz), 2.61(2H, t, J=7.1 Hz), 3.71(3H, s), 3.75(2H, s),4.07(2H, t, J=7.1 Hz), 4.22(4H, q, J=7.1 Hz), 6.94(1H, d, J=7.6 Hz),7.29-7.62(13H, m), 7.72(1H, dd, J=1.4, 7.6 Hz), 8.47(1H, d, J=8.3 Hz),10.25(1H, brs) 5-18

1.13(3H, t, J=7.2 Hz), 1.23(6H, t, J=7.1 Hz), 2.30(3H, s), 2.61(2H, t,J=7.1 Hz), 3.25(2H, q, J=7.2 Hz), 3.44(2H, s), 4.07(2H, t, J=7.1 Hz),4.21(4H, q, J=7.1 Hz), 6.75(1H, s), 7.30-7.69(14H, m), 8.19(1H, brs)

Example 6 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]benzoic acid2-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]ethyl ester a)4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]benzoic acid ethyl ester

4-Aminobenzoic acid ethyl ester (0.568 g) and triethylamine (0.570 g)were dissolved in methylene chloride (20 mL), and to this solution wasdropwise added a solution of 4′-trifluoromethylbiphenyl-2-carboxylicacid chloride, which is prepared from4′-trifluoromethylbiphenyl-2-carboxylic acid (1.00 g) in a similarmanner to Example 1d), in methylene chloride under ice-cooling. Thesolution was stirred at room temperature for 2 hours, followed byaddition of methylene chloride (100 mL). The reaction mixture was washedwith 2N hydrochloric acid and saturated brine, dried over sodium sulfateand concentrated to give the title compound (1.43 g).

b) 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]benzoic acid

The 4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]benzoic acid ethylester (0.700 g) obtained in Example 6a) was subjected to reactionssimilar to Example 1f) to give the title compound (0.680 g) as a whitesolid.

c) 9-[2-(Tert-butyldimethylsilanyloxy)ethyl]-9H-fluoren-9-carboxylicacid (2,2,2-trifluoroethyl)amide

9H-Fluorene-9-carboxylic acid (2,2,2-trifluoroethyl)amide (3.00 g) wasdissolved in tetrahydrofuran (100 mL), and to this solution was addeddropwise a 1.5M solution (13.7 mL) of lithium diisopropylamide underice-cooling. The mixture was stirred for one hour under ice-cooling, andto this was added a solution of tert-butyldimethylsilanyloxyethylbromide (2.46 g) in tetrahydrofuran (5 mL). The temperature wasgradually raised from under ice-cooling to room temperature, and themixture was stirred overnight. Saturated aqueous ammonium chloride wasadded to the reaction mixture under ice-cooling and then extracted withethyl acetate (50 mL×2). The extract was washed with saturated brine,dried over sodium sulfate and purified by column chromatography onsilica gel with ethyl acetate:hexane=1:2.5 to give the title compound(6.00 g).

d) 9-(2-Hydroxyethyl)-9H-fluoren-9-carboxylic acid(2,2,2-trifluoroethyl)amide

The 9-[2-(Tert-butyldimethylsilanyloxy)ethyl]-9H-fluoren-9-carboxylicacid (2,2,2-trifluoroethyl)amide (6.00 g) obtained in Example 6c) wasdissolved in tetrahydrofuran (13 mL)—acetic acid (39 mL)—water (13 mL).The solution was stirred at room temperature for 20 hours andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel with ethyl acetate:hexane=1:1 to give the title compound(3.80 g).

e) 4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino]benzoic acid2-[9-(2,2,2-trifluoromethylcarbamoyl)-9H-fluoren-9-yl]ethyl ester

The 4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]benzoic acid (0.345g) obtained in Example 6b) and the9-(2-hydroxyethyl)-9H-fluoren-9-carboxylic acid(2,2,2-trifluoroethyl)amide (0.300 g) obtained in Example 6d) weresubjected to reactions similar to those in Example 1g) to give the titlecompound (0.390 g) as a colorless solid (see Table 52).

Examples 6-2 to 6-22

Compounds of Examples 6-2 to 6-22 were obtained in a similar manner toExamples 6, 1-2b), 1-2c) and 1-2d). The compounds thus obtained wereshown in Tables 52 to 56.

TABLE 52 Example Structure NMR (δ, 300 MHz, CDCl₃) 6

2.98(2H, t, J=6.8 Hz), 3.63-3.71(2H, m), 3.81(2H, t, J=6.8 Hz), 5.27(1H,br), 7.00(1H, brs), 7.12(2H, m), 7.30-7.84(18H, m). 6-2

2.45-2.58(2H, m), 4.10-4.18(1H, m), 4.21(2H, t, J=7.5 Hz), 7.02(1H,brs), 7.14-7.88(20H, m). 6-3

3.01(2H, t, J=6.6 Hz), 3.60-3.74(2H, m), 3.86(2H, t, J=6.6 Hz),5.27(18H, m), 7.20-7.61(18H, m), 7.75(2H, d, J=6.6 Hz), 7.97(1H, brs),8.52(1H, d, J=8.4 Hz). 6-4

3.56(2H, t, J=5.2 Hz), 4.06(2H, t, J=5.2 Hz), 5.52(1H, br), 7.08(1H,brs), 7.15-7.98(21H, m). 6-5

3.42-3.54(2H, m), 3.55(2H, s), 4.26(2H, t, J=6.6 Hz), 5.52(1H, br),7.06(1H, brs), 7.18-7.88(21H, m).

TABLE 53 Example Structure NMR (δ, 300 MHz, CDCl₃) 6-6

2.31-2.42(1H, m), 2.80-2.93(1H, m), 3.73-3.89(2H, m), 4.16-4.26(1H, m),4.32-4.43(2H, m), 5.62(1H, br), 7.09((1H, brs), 7.26-8.01(19H, m). 6-7

2.15-2.29(2H, m), 3.34(2H, t, J=7.9 Hz), 4.01-4.18(2H, m), 4.40(2H, t,J=6.2 Hz), 6.15(1H, br), 7.08(1H, brs), 7.18-7.98(17H, m), 7.92(1H, d,J=8.4 Hz). 6-8

2.88(2H, t, J=8.3 Hz), 3.83-3.93(2H, m), 4.23(2H, t, J=8.3 Hz), 5.90(1H,t, J=6.4 Hz), 7.01(1H, brs), 7.16-7.86(22H, m). 6-9

2.12-2.29(1H, m), 2.56-2.68(1H, m), 3.70-3.80(3H, m), 4.09-4.29(2H, m),5.41(1H, br), 7.05(1H, brs), 7.12-7.78(20H, m), 7.86(1H, d, J=7.5 Hz).6-10

2.16-2.30(2H, m), 2.62-2.72(2H, m), 3.61(1H, t, J=7.5 Hz), 3.71-3.99(4H,m), 4.12-4.37(4H, m), 5.67(1H, br), 7.05(1H, brs), 7.15-7.91(17H, m).

TABLE 54 Example Structure NMR (δ, 300 MHz, CDCl₃) 6-11

3.49(2H, t, J=6.9 Hz), 4.09-4.29(2H, m), 4.56(2H, t, J=6.9 Hz), 6.34(1H,br). 7.08(1H, brs), 7.12-8.00(18H, m). 6-12

2.39-2.50(1H, m), 2.93-3.05(1H, m), 3.78-4.06(2H, m), 4.20-4.41(2H, m),4.77(1H, d, J=6.4 Hz, J=9.6 Hz), 5.42(1H, 1H, t, J=6.4 Hz), 7.07(1H,brs), 7.19-7.88(15H, m). 6-13

2.19-2.30(1H, m), 2.62-2.73(1H, m), 3.79-3.82(2H, m), 4.20-4.40(3H, m),5.80(1H, t, J=6.4 Hz), 7.06(1H, brs), 7.16-7.92(16H, m). 6-14

1.22(6H, t, J=7.1 Hz), 2.77(2H, t, J=6.9 Hz), 4.21(4H, q, J=7.12 Hz),4.30(2H, t, J=6.9 Hz), 7.06(1H, brs), 7.19-7.88(17H, m) 6-15

1.23(6H, t, J=7.1 Hz), 1.64(3H, s), 2.77(2H, t, J=6.9 Hz), 4.21(4H, q,J=7.1 Hz), 4.29(2H, t, J=6.9 Hz), 6.93(1H, brs), 7.20-8.24(16H, m)

TABLE 55 Example Structure NMR (δ, 300 MHz, CDCl₃) 6-16

1.22(3H, t, J=7.1 Hz), 1.23(3H, t, J=7.1 Hz), 2.76(2H, t, J=6.9 Hz),4.20(2H, q, J=7.1 Hz), 4.21(2H, q, J=7.1 Hz), 4.29(2H, t, J=6.9 Hz),6.95-7.91(17H, m) 6-17

1.22(6H, t, J=7.1 Hz), 2.77(2H, t, J=6.9 Hz), 4.20(4H, q, J=7.1 Hz),4.31(2H, t, J=6.9 Hz), 6.93(2H, d, J=8.8 Hz), 7.26-8.13(13H, m),7.92(2H, d, J=8.8 Hz) 6-18

1.22(6H, t, J=7.1 Hz), 2.76(2H, t, J=6.9 Hz), 4.20(4H, q, J=7.1 Hz),4.30(2H, t, J=6.9 Hz), 6.85(2H, d, J=8.8 Hz), 7.21-7.81(13H, m),7.88(2H, d, J=8.8 Hz), 8.21(1H, dd, J=7.6, 1.3) 6-19

1.14(6H, t, J=7.2 Hz), 2.63-2.71(2H, m), 3.31(4H, dq, J=5.6, 7.2 Hz),4.29-4.38(2H, m), 7.15-7.20(1H, m), 7.23-7.38(7H, m), 7.41-7.47(1H, m),7.49-7.63(4H, m), 7.64-7.75(4H, m), 7.81(1H, dd, J=1.5, 7.5 Hz),7.86-7.93(2H, m) 6-20

1.14(6H, t, J=7.1 Hz), 2.65-2.74(2H, m), 3.31(4H, dq, J=5.7, 7.1 Hz),4.33-4.43(2H, m), 7.08(1H, d, J=8.3 Hz), 7.27-7.44(6H, m), 7.47-7.61(5H,m), 7.63-7.72(3H, m), 7.90(1H, dd, J=1.9, 8.6 Hz), 8.07(1H, d, J=1.9Hz), 8.23(1H, dd, J=1.5, 7.9 Hz)

TABLE 56 Example Structure NMR (δ, 300 MHz, CDCl₃) 6-21

1.14(6H, t, J=7.2 Hz), 2.64-2.73(2H, m), 3.32(4H, dq, J=5.6, 7.2 Hz),4.31-4.41(2H, m), 6.91-6.98(2H, m), 7.26-7.36(5H, m), 7.41(1H, dd,J=1.1, 7.5 Hz), 7.47-7.59(3H, m), 7.60-7.71(5H, m), 7.94-8.01(2H, m),8.11(1H, dd, J=1.1, 7.5 Hz) 6-22

1.13(6H, t, J=7.2 Hz), 2.66-2.75(2H, m), 3.32(4H, dq, J=5.3, 7.2 Hz),4.36-4.45(2H, m), 7.27-7.46(8H, m), 7.48-7.54(2H, m), 7.55-7.73(4H, m),7.99(2H, s), 8.32(1H, dd, J=1.1, 7.9 Hz)

Example 7Trans-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]cyclohexanecarboxylicacid 2-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]ethyl ester a)4-[(4′-Trifluoromethylbiphenyl-2-carbonyl)amino)cyclohexanecarboxylicacid

4-Amino-cyclohexanecarboxylic acid (0.538 g) was dissolved in 4N sodiumhydroxide (0.933 mL), and to this solution were dropwise addedsimultaneously a solution of the acid chloride which is obtained from4′-trifluoromethylbiphenyl-2-carboxylic acid (1.0 g) in a similar mannerto Example 1d) in tetrahydrofuran (5 mL) and 4N aqueous sodium hydroxide(0.933 mL) under ice-cooling. The mixture was stirred at roomtemperature for one hour, acidified with 2N hydrochloric acid andextracted with ethylacetate. The extract was washed with saturated brineand dried over sodium sulfate to give the title compound (1.20 g) as acolorless powdery solid.

b)Trans-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]cyclohexanecarboxylicacid 2-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]ethyl ester

The4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]cyclohexanecarboxylicacid (0.570 g) obtained in Example 7a) and9-(2-hydroxyethyl)-9H-fluoren-9-carboxylic acid(2,2,2-trifluoroethyl)amide (0.500 g) obtained in Example 6d) weretreated in a similar manner to Example 1g) to give the title compound(0.534 g) as a colorless solid (see Table 57).

Examples 7-2 to 7-5

Compounds of Examples of 7-2 to 7-5 were obtained in a similar manner toExample 7. The compounds thus obtained were shown in Table 57.

TABLE 57 Example Structure NMR (δ, 300 MHz, CDCl₃) 7

1.08-1.20(4H, m), 1.28-1.42(4H, m), 1.87-1.94(1H, m), 2.80(2H, t, J=7.1Hz), 3.52(2H, t, J=7.1 Hz), 3.65(1H, m), 3.89(1H, br), 5.18(1H, d, J=8.3Hz), 5.25(1H, t, J=6.4 Hz), 7.29-7.79(16H, m). 7-2

0.60-0.71(2H, m), 1.05-1.27(2H, m), 1.53-1.86(4H, m), 2.82(2H, t,6.9Hz), 3.54(2H, t, J=6.9 Hz), 3.56-3.73(2H, m), 4.96(1H, d, J=8.3 Hz),5.27(1H, t, J=7.7 Hz), 7.30-7.80(16H, m). 7-3

1.33-1.73(8H, m), 2.00-2.13(1H, m), 2.22-2.37(1H, m), 2.45-2.60(1H, m),3.52(1H, t, J=7.0 Hz), 3.66-4.11(4H, m), 5.30(1H, d, J=11.3 Hz),5.72(1H, t, J=8.2 Hz), 7.20-7.33(13H, m). 7-4

1.09-1.20(2H, m), 1.24(6H, t, J=7.2 Hz), 1.36-1.53(6H, m), 2.27-2.38(1H,m), 3.82-3.95(1H, m), 4.22(4H, q, J=7.2 Hz), 4.80(2H, s), 5.21(1H, br-d,J=7.9 Hz), 7.22-7.39(6H, m), 7.42-7.57(4H, m), 7.60-7.70(3H, m) 7-5

1.12-2.27(9H, m), 1.24(6H, t, J=7.2 Hz), 2.60(2H, t, J=7.2 Hz),3.59-3.78 and 3.90-4.15(1H, m), 4.02(2H, t, J=7.2 Hz), 4.22(4H, q, J=7.2Hz), 4.98 and 5.30(1H, each d, J=8.4 Hz), 7.18-7.22(13H, m) cis, transmixture

Example 82-Phenyl-2-(2-{4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]piperidin-1-yl}acetoxymethyl)malonicacid diethyl ester a)1-Benzyl-4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidine

4′-Trifluoromethyl-biphenyl-carboxylic acid (5.0 g) was dissolved indimethylformamide (50 mL), and to this solution were added at roomtemperature 4-amino-1-benzylpiperidine (3.55 g), 1-hydroxybenzotriazolehydrate (3.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (3.58 g). The mixture was stirred at room temperatureovernight, and the reaction solution was concentrated in vacuo toprecipitate crystals. The crystals were washed successively withsaturated aqueous sodium bicarbonate and water, and dried in vacuo togive the title compound (7.42 g).

b) 4-(4′-Trifluoromethylbiphenyl-2-carbonylamino)piperidine

To a solution of the1-benzyl-4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidine (1.47g) obtained in Example 8a) in tetrahydrofuran-methanol (1:1; 50 mL) wasadded palladium hydroxide (300 mg) in a stream of argon underice-cooling. The mixture was stirred for one day at normal pressureunder hydrogen atmosphere, and further stirred for one day at normalpressure under hydrogen atmosphere after further addition of palladiumhydroxide (300 mg). The reaction mixture was filtered through a Celitepad and washed with methanol. The filtrate and the washings werecombined, concentrated in vacuo and purified by column chromatography onsilica gel with chloroform:methanol:aqueous ammonia=100:10:1 to give thetitle compound (1.03 g).

c) [4-(4′-Trifluoromethylbiphenyl-2-carbonyl-amino)piperidin-1-yl]aceticacid ethyl ester

To a solution of4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidine (1.03 g)obtained in Example 8b) in dimethylformamide (5 mL) were added potassiumcarbonate (276 mg) and bromoacetic acid ethyl ester (223 μL). Themixture was stirred overnight at ambient temperature of 90° C., and thenconcentrated in vacuo. The residue was distributed with water andchloroform, and the aqueous layer was further extracted with chloroform.The organic layers were combined, washed with saturated brine, driedover sodium sulfate, concentrated in vacuo and purified by columnchromatography on silica gel with chloroform:methanol=30:1 to give thetitle compound (598 mg).

d) [4-(4′-Trifluoromethylbiphenyl-2-carbonyl-amino)piperidin-1-yl]aceticacid

To a solution of[4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidin-1-yl]aceticacid ethyl ester (595 mg) obtained in Example 8c) intetrahydrofuran-methanol (1:2; 10.2 mL) was added 1M aqueous lithiumhydroxide (6.8 mL), and the mixture was stirred at room temperature for6 hours. The reaction solution was concentrated in vacuo and 2Nhydrochloric acid was added to the residue to adjust the pH to about 3,thereby crystals were precipitated. The crystals were collected byfiltration, washed with cold water and dried in vacuo to give the titlecompound (411 mg).

e)2-Phenyl-2-(2-{4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]piperidin-1-yl}acetoxymethyl)malonicacid diethyl ester

The[4-(4′-trifluoromethylbiphenyl-2-carbonyl-amino)piperidin-1-yl]aceticacid obtained in Example 8d) and the 2-hydroxymethyl-2-phenylmalonicacid diethyl ester obtained in Example 1-2a) were subjected to reactionssimilar to those in Example 1g) to give the title compound (90 mg) (seeTable 58).

TABLE 58 Example Structure NMR (δ, 300 MHz, CDCl₃) 8

1.07-1.19(2H, m), 1.25(6H, t, J=7.0 Hz), 1.54-1.68(2H, m), 2.10-2.22(2H,m), 2.52-2.62(2H, m), 3.08(2H, s), 3.70-3.85(1H, m), 4.24(4H, q, J=7.0Hz), 4.85(2H, s), 5.07-5.16(1H, m), 7.28-7.39(6H, m), 7.42-7.57(4H, m),7.61-7.71(3H, m)

Example 92-Phenyl-2-(2-{4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]indol-1-yl}acetoxymethyl)malonicacid diethyl ester a) (4-Nitroindol-1-yl)acetic acid ethyl ester

Sodium hydride (60%/mineral oil: 81 mg) was dissolved indimethylformamide (5 mL), and the solution was cooled to 0° C. Afteraddition of 4-nitroindole (300 mg), the mixture was stirred for onehour, and bromoacetic acid ethyl ester (340 mg) was added thereto,followed by stirring at 0° C. for 4 hours. Water was added thereto andthe mixture was concentrated, diluted with ethyl acetate, washed withwater, dried over sodium sulfate, then concentrated to give the titlecompound (367 mg)

b) (4-Nitroindol-1-yl)acetic acid

The (4-nitroindol-1-yl)acetic acid ethyl ester obtained in Example 9a)was subjected to reactions similar to those in Example 1f) to give thetitle compound (243 mg).

c) 2-[2-(3-Nitroindol-1-yl)acetoxymethyl]-2-phenylmalonic acid diethylester

The (4-nitroindol-1-yl)acetic acid (229 mg) obtained in Example 9b),4-dimethylaminopyridine (143 mg) and the 2-hydroxymethyl-2-phenylmalonicacid diethyl ester (240 mg) obtained in Example 1-2a) were subjected toreactions similar to those in Example 1-3c) to give the title compound(301 mg).

d) 2-[2-(4-Aminoindol-1-yl)acetoxymethyl]-2-phenylmalonic acid diethylester

The 2-[2-(3-Nitroindol-1-yl)acetoxymethyl]-2-phenylmalonic acid diethylester (100 mg) obtained in Example 9c) was dissolved in tetrahydrofuran(2 mL), ethanol (4 mL) and water (1 mL), and to the solution were addedammonium chloride (57 mg) and reduced iron (60 mg). The mixture wasstirred at 100° C. for 2 hours, cooled, and filtered through a Celitepad. The filtrate was concentrated and diluted with ethyl acetate. Theextract was washed successively with saturated aqueous sodiumbicarbonate, water and saturated brine, dried over sodium sulfate, andconcentrated to give the title compound (93 mg).

e)2-Phenyl-2-(2-{4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]indol-1-yl}acetoxymethyl)malonicacid diethyl ester

The 2-[2-(4-aminoindol-1-yl)acetoxymethyl]-2-phenylmalonic acid diethylester obtained in Example 9d) was treated in a similar manner to Example1e) to give the title compound (119 mg) (see Table 59).

Example 9-22-(2-{2-methyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl}amino]benzimidazol-1-yl}acetoxymethyl)-2-phenyl-malonicacid diethyl ester a) 2-Methyl-4-nitro-1H-benzimidazole

3-Nitrobenzene-1,2-diamine (1.0 g) was dissolved in ethanol (90 mL) and5N hydrochloric acid (24 mL), and to this solution was added2,4-pentanedione (1.3 g). The mixture was heated for 3 hours underreflux, cooled down to room temperature and concentrated. To thisconcentrate was added ethyl acetate, and the mixture was washedsuccessively with saturated aqueous sodium bicarbonate and water, anddried over sodium sulfate to give the title compound (1.1 g).

b) (2-Methyl-4-nitrobenzimidazol-1-yl)acetic acid ethyl ester

The 2-methyl-4-nitro-1H-benzimidazole (1.1 g) obtained in Example 9-2a)was subjected to reactions similar to those in Example 9a) to give thetitle compound (1.44 g).

c)2-(2-{2-Methyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]benzimidazol-1-yl}acetoxymethyl)-2-phenyl-malonicacid diethyl ester

The (2-Methyl-4-nitrobenzimidazol-1-yl)acetic acid ethyl ester (500 mg)obtained in Example 9-2b) was subjected to reactions similar to those inExamples 9d), 1d), 1e), 1f) and 1g) to give the title compound (152 mg)(see Table 59).

Example 9-3[2-Oxo-3-(4′-trifluoromethylbiphenyl-2-carbonyl)-2,3-dihydrobenzoxazol-6-yl]aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester

The{3-Hydroxy-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}aceticacid 2,2-bisethylcarbamoyl-2-phenylethyl ester (195 mg) obtained inExample 3-2was dissolved in chloroform (5 mL), and to this solution wasadded triethylamine (72 mg). The solution was cooled to 0° C. andtriphosgene (35 mg) was added thereto. After stirring for one hour, thereaction solution was washed with water, dried over sodium sulfate andpurified by column chromatography on silica gel with hexane:ethylacetate=1:1 to give the title compound (173 mg) (see Table 59).

Example 9-42-(2-{3-Ethoxycarbonyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester a) 5-Chloro-2-nitrobenzoic acid chloride

5-Chloro-2-nitrobenzoic acid was subjected to reactions similar to thosein Example 1d) to give the title compound.

b) 5-Chloro-2-nitrobenzoic acid ethyl ester

To a mixture of ethanol (1.23 mL), triethylamine (3.05 mL) andtetrahydrofuran (35 mL) was dropwise added a solution of5-chloro-2-nitrobenzoic acid chloride (4.44 g) obtained in Example 9-4a)in tetrahydrofuran (10 mL) under ice-cooling. The mixture was stirred atroom temperature overnight, and water was then added. The solution wasdiluted with ethyl acetate, and the organic layer was washedsuccessively with saturated aqueous sodium bicarbonate and saturatedbrine, dried over sodium sulfate and concentrated to give the titlecompound (4.43 g) as a pale brown solid.

c) 3-Ethoxycarbonyl-4-nitrophenylmalonic acid dibenzyl ester

The 5-chloro-2-nitrobenzoic acid ethyl ester (4.40 g) obtained inExample 9-4b) and malonic acid dibenzyl ester were subjected toreactions similar to those in Example 1-3a) to give the title compound(4.61 g).

d) 4-Amino-3-ethoxycarbonylphenylacetic acid

The 3-ethoxycarbonyl-4-nitrophenylmalonic acid dibenzyl ester (1.51 g)obtained in Example 9-4c) was subjected to reactions similar to those inExample 1-3d) to give the title compound (4.59 g).

e)3-Ethoxycarbonyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylaceticacid

The 4-amino-3-ethoxycarbonylphenylacetic acid (1.51 g) obtained inExample 9-4d) and 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride(1.99 g) were subjected to reactions similar to those in Example 7a)with the proviso that sodium bicarbonate was used as a base, thereby thetitle compound (1.87 g) was given as a pale yellow amorphous powder.

f)2-(2-{3-Ethoxycarbonyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonicacid diethyl ester

The3-ethoxycarbonyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenylaceticacid (0.532 g) obtained in Example 9-4e) and the2-hydroxymethyl-2-phenylmalonic acid diethyl ester (1.04 g) obtained inExample 1-2a) were treated in a similar manner to Example 1g) to givethe title compound (0.524 g) (see Table 59).

Example 9-52-(3-{3-Dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonicacid diethyl ester a) 5-Methyl-2-nitrobenzoic acid chloride

5-Methyl-2-nitrobenzoic acid was treated in a similar manner to Example1d) to give the title compound.

b) 5, N,N-Trimethyl-2-nitrobenzamide

The 5-methyl-2-nitrobenzoic acid chloride obtained in Example 9-5a) wastreated in a similar manner to Example 1e) to give the title compound.

c) 5-Bromomethyl-N,N-dimethyl-2-nitrobenzamide

The 5, N,N-Trimethyl-2-nitrobenzamide (4.16 g) obtained in Example9-5b), N-bromosuccinimide (3.56 g) and 2,2′-azobisisobutyronitrile (328mg) were suspended in carbon tetrachloride (80 mL). The suspension wasstirred at 90° C. for 2 hours, filtered through a Celite pad andpurified by column chromatography on silica gel with hexane:ethylacetate=5:4 to give the title compound (602 mg).

d) 3-(3-Dimethylcarbamoyl-4-nitrophenyl)-2-methoxy-carbonylpropionicacid benzyl ester

The 5-bromomethyl-N,N-dimethyl-2-nitrobenzamide (0.597 g) obtained inExample 9-5c) and malonic acid benzyl ester methyl ester were subjectedto reactions similar to those in Example 9-4c) to give the titlecompound (0.491 g).

e) 3-(4-Amino-3-dimethylcarbamoylphenyl)-2-methoxycarbonyl-propionicacid

The 3-(3-dimethylcarbamoyl-4-nitrophenyl)-2-methoxycarbonyl-propionicacid benzyl ester (0.490 g) obtained in Example 9-5d) was subjected toreactions similar to those in Example 1-2c) to give the title compound(0.353 g).

f) 3-(4-Amino-3-dimethylcarbamoylphenyl)propionic acid methyl ester

The 3-(4-amino-3-dimethylcarbamoylphenyl)-2-methoxycarbonylpropionicacid (347 mg) obtained in Example 9-5e) was stirred at 150° C. for 40minutes, cooled down to room temperature, and purified by columnchromatography on silica gel with hexane:ethyl acetate (1:1 to 0:1) togive the title compound (180 mg).

g)2-(3-{3-Dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}propionyloxymethyl)-2-phenylmalonicacid diethyl ester

The 3-(4-amino-3-dimethylcarbamoylphenyl)propionic acid methyl ester(0.138 g) obtained in Example 9-5f) was subjected to reactions similarto those in Examples 1e), 1f) and 1g) to give the title compound (0.158g) (see Table 59).

Examples 9-6 to 9-29

Compounds of Examples 9-6 to 9-29 were obtained in a similar manner toExamples 9 to 9-5. The compounds thus obtained were shown in Tables 59to 64.

TABLE 59 Example Structure NMR (δ, 300 MHz, CDCl₃) 9

1.18(6H, t, J=7.2 Hz), 4.15 (4H, q, J=7.2 Hz), 4.73(2H, s), 4.85(2H, s),5.56(1H, d, J=3.0 Hz), 6.85(1H, d, J=3.4 Hz), 6.91(1H, d, J=8.3 Hz),7.16-7.78(16H, m), 7.92(1H, d, J=6.8 Hz) 9-2

1.17(6H, t, J=7.1 Hz), 2.38 (3H, s), 4.13(4H, q, J=7.1 Hz), 4.70(2H, s),4.87(2H, s), 6.84(1H, d, J=7.9 Hz), 7.12-7.63(13H, m), 7.80 (1H, dd,J=7.5, 1.5 Hz), 8.18(1H, d, J=7.9 Hz), 8.41 (1H, s) 9-3

1.08(6H, t, J=7.2 Hz), 3.27 (4H, dq, J=7.2, 7.2 Hz), 3.61(2H, s),4.88(2H, s), 6.93(1H, d, J=1.1 Hz), 7.04 (1H, dd, J=8.3, 1.5 Hz),7.11-7.70(15H, m), 7.79 (1H, d, J=8.3 Hz) 9-4

1.21(6H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 3.55(2H, s),4.15-4.30(6H, m), 4.83 (2H, s), 7.24-7.38(6H, m), 7.41-7.47(1H, m),7.48-7.62(6H, m), 7.76 (1H, dd, J=1.5, 7.5 Hz), 7.81(1H, d, J=1.9 Hz),8.68 (1H, d, J=8.7 Hz), 11.23 (1H, br-s) 9-5

1.24(6H, t, J=7.0 Hz), 2.53 (2H, t, J=7.3 Hz), 2.76- 3.00(6H, br),2.81(2H, t, J= 7.3 Hz), 4.24(4H, q, J=7.0 Hz), 4.81(2H, s), 6.96(1H, d,J=2.3 Hz), 7.17(1H, dd, J=1.2, 8.4 Hz), 7.29-7.37 (5H, m), 7.37-7.42(1H,m), 7.44-7.57(2H, m), 7.60-7.64(4H, m), 7.68 (1H, dd, J=1.5, 7.4 Hz),8.28(1H, d, J=8.4 Hz), 9.05 (1H, br-s)

TABLE 60 Example Structure NMR (δ, 300 MHz, CDCl₃) 9-6 

1.12(6H, t, J=7.2 Hz), 3.30 (4H, dq, J=5.7, 7.2 Hz), 4.39(2H, d, J= 6.0Hz), 5.08(2H, s), 5.59(1H, br-t, J=6.0 Hz), 6.97-7.03(2H, m),7.28-7.42(8H, m), 7.43-7.55(4H, m), 7.56-7.61(2H, m), 7.66-7.71(1H, m),7.76-7.83(2H, m) 9-7 

1.08(3H, t, J=7.2 Hz), 2.64-2.82(2H, m), 2.86-2.97(2H, m), 3.13-3.36(2H,m), 5.87-5.98(1H, br), 6.03(1H, s), 7.00(1H, s), 7.04-7.15 (4H, m),7.30-7.40 (5H, m), 7.43(1H, dd, J=1.1, 7.5 Hz), 7.48-7.63(4H, m),7.63-7.71(2H, m), 7.78 (1H, dd, J= 1.5, 7.5 Hz) 9-8 

1.04(6H, t, J=7.2 Hz), 3.23 (4H, dq, J=5.7, 7.2 Hz), 3.55(2H, s),4.85(2H, s), 5.23(2H, s), 7.08(2H, br-t, J= 5.7 Hz), 7.14-7.22(2H, m),7.23-7.47(10H, m), 7.48-7.64(6H, m), 7.76(1H, dd, J=1.5, 7.1 Hz),7.81(1H, d, J=2.2 Hz), 8.69(1H, d, J=8.7 Hz), 11.17(1H, br-s) 9-9 

1.05(6H, t, J=7.2 Hz), 3.25 (4H, dq, J=5.6, 7.2 Hz), 3.58(2H, s),4.86(2H, s), 7.11- 7.63(15H, m), 7.72(1H, dd, J=1.5, 7.5 Hz), 7.83(1H,dd, J=1.9 Hz), 8.66(1H, d, J=8.6 Hz), 11.10(1H, br-s) 9-10

1.07(6H, t, J=7.2 Hz), 1.36 (3H, t, J=7.2 Hz), 3.26(4H, dq, J= 5.4, 7.2Hz), 3.58(2H, s), 4.26(2H, q, J=7.2 Hz), 4.86(2H, s), 7.10(2H, br-t,J=5.4 Hz), 7.16-7.37(6H, m), 7.40-7.64(7H, m), 7.77(1H, dd, J=1.9, 7.1Hz), 7.80(1H, d, J=1.9 Hz), 8.69(1H, d, J=8.7 Hz), 11.22(1H, br-s)

TABLE 61 Example Structure NMR (δ, 300MHz, CDCl₃) 9-11

1.19(6H, t, J=7.2Hz), 4.17(4H, q, J=7.2Hz), 4.79(2H, s), 4.90(2H, s),6.94(1H, d, J=8.0Hz), 7.15–7.63(13H, m), 7.82(1H, d, J=7.5Hz), 8.25(1H,d, J=8.0Hz), 8.47(1H, br.s) 9-12

1.15(6H, t, J=7.2Hz), 2.64–2.73(2H, m), 3.32(4H, dq, J=5.3, 7.2Hz),4.31–4.44(2H, m), 4.41(2H, d, J=6.0Hz), 5.62(1H, br-t, J=6.0Hz),7.10–7.16(1H, m), 7.24–7.39(7H, m), 7.42–7.58(6H, m), 7.62–7.72(3H, m),7.74–7.78(1H, m), 7.85–7.92(1H, m) 9-13

1.07(6H, t, J=7.1Hz), 3.26(4H, dq, J=5.7, 7.1Hz), 3.57(2H, s), 3.81(3H,s), 4.86(2H, s), 7.10(6H, br-t, J=5.7Hz), 7.16–7.23(2H, m),7.25–7.37(4H, m), 7.41–7.63(7H, m), 7.77(1H, dd, J=1.5, 7.5Hz), 7.80(1H,d, J=2.2Hz), 8.68(1H, d, J=8.3Hz), 11.15(1H, br-s) 9-14

1.19(6H, t, J=7.0Hz), 3.52(2H, s), 4.19(4H, q, J=7.0Hz), 4.82(2H, s),5.23(2H, s), 7.24–7.29(5H, m), 7.32–7.46(7H, m), 7.49–7.62(6H, m),7.74–7.79(1H, m), 7.82(1H, d, J=2.2Hz), 8.67(1H, d, J=8.8Hz), 11.17(1H,br-s) 9-15

1.21(6H, t, J=7.1Hz), 3.56(2H, s), 4.21(4H, q, J=7.1Hz), 4.85(2H, s),7.23–7.32(5H, m), 7.36–7.63(8H, m), 7.77(1H, dd, J=1.5, 7.5Hz), 7.86(1H,d, J=1.9Hz), 8.70(1H, br-d, J=8.3Hz), 10.89(1H, br-s)

TABLE 62 Example Structure NMR (δ, 300MHz, CDCl₃) 9-16

1.22(6H, t, J=7.1Hz), 3.57(2H, s), 4.23(4H, q, J=7.1Hz), 4.85(2H, s),6.92(1H, s), 7.03(1H, d, J=8.3Hz), 7.30–7.69(13H, m), 7.77(1H, d,J=8.3Hz) 9-17

1.23(6H, t, J=7.1Hz), 3.67(2H, s), 4.23(4H, q, J=7.1Hz), 4.85(2H, s),7.23–7.34(6H, m), 7.42–7.49(3H, m), 7.52–7.67(5H, m), 7.95(1H, d,J=1.9Hz), 8.05(1H, dd, J=1.5, 7.5Hz) 9-18

1.21(6H, t, J=7.2Hz), 1.31(6H, d, J=6.4Hz), 3.55(2H, s), 4.21(4H, q,J=7.2Hz), 4.83(2H, s), 5.09(1H, sept, J=6.4Hz), 7.24–7.38(6H, m),7.41–7.47(1H, m), 7.48–7.62(6H, m), 7.73–7.81(2H, m), 8.68(1H, d,J=8.6Hz), 11.33(1H, br-s) 9-19

1.21(6H, t, J=7.1Hz), 3.54(2H, s), 3.80(3H, s), 4.21(4H, q, J=7.1Hz),4.83(2H, s), 7.24–7.38(6H, m), 7.44(1H, dd, J=1.6, 7.1Hz), 7.50–7.62(6H,m), 7.77(1H, dd, J=1.5, 7.1Hz), 7.81(1H, d, J=2.3Hz), 8.67(1H, d,J=8.7Hz), 11.15(1H, br-s) 9-20

1.21(6H, t, J=7.1Hz), 1.85–2.03(2H, m), 2.05–2.27(2H, m), 2.50–2.67(1H,m), 2.81(3H, brs), 2.88(3H, brs), 3.02–3.16(1H, m), 3.51(2H, s),3.71–3.86(1H, m), 4.20(4H, q, J=7.1Hz), 4.82(2H, s), 6.99(1H, d,J=9.0Hz), 7.05(1H, d, J=1.8 Hz), 7.18(1H, dd, J=1.9Hz, J=8.3Hz),7.22–7.37(5H, m), 7.56(1H, dd, J=1.8H, J=9.0Hz), 8.01(1H, brs), 8.08(1H,d, J=8.3Hz), 9.29(1H, brs).

TABLE 63 Example Structure NMR (δ, 300MHz, CDCl₃) 9-21

1.18(6H, t, J=7.1Hz), 2.03(3H, s), 3.53(2H, s), 4.14(4H, q, J=7.1Hz),4.86(2H, s), 6.97–7.05(2H, m), 7.24–7.81(15H, m), 8.35(1H, brs). 9-22

1.20(6H, t, J=7.2Hz), 3.52(2H, s), 3.72(3H, s), 4.18(4H, q, J=7.2Hz),4.83(2H, s), 6.83(1H, brs), 4.95(1H, dd, J=1.8Hz, J=8.3Hz), 7.14(1H, d,J=8.3Hz), 7.18=7.80(15H, m). 9-23

1.20(6H, t, J=7.1Hz), 2.36(3H, s), 3.57(2H, s), 4.20(4H, q, J=7.1Hz),4.85(2H, s), 6.85(1H, s), 7.18–7.59(14H, m), 8.67(1H, d, J=8.6Hz),12.71(1H, brs) 9-24

1.19(6H, t, J=7.2Hz), 3.53(2H, s), 4.17(4H, q, J=7.2Hz), 4.82(2H, s),6.89–6.96(3H, m), 7.17–7.55(17H, m), 7.67(1H, dd, J=1.5, 7.5Hz),8.45(1H, d, J=8.7Hz) 9-25

1.21(6H, t, J=7.1Hz), 3.59(2H, s), 4.21(4H, q, J=7.1Hz), 4.87(2H, s),7.27–7.78(15H, m), 8.67(1H, d, J=8.3Hz), 9.61(1H, brs), 11.1(1H, brs)

TABLE 64 Example Structure NMR (δ, 300MHz, CDCl₃) 9-26

1.20(6H, t, J=7.0Hz), 1.94(6H, s), 3.14(2H, s), 3.48(2H, s), 4.19(4H, q,J=7.0Hz), 4.81(2H, s), 6.83(1H, d, J=2.0Hz), 7.08(1H, dd, J=2.0, 8.0Hz),7.27–7.59(12H, m), 7.68(1H, dd, J=1.2, 7.6Hz), 8.22(1H, d, J=8.5Hz),10.7(1H, brs) 9-27

1.21(6H, t, J=7.1Hz), 3.20(3H, s), 3.36(3H, s), 3.52(2H, s), 4.21(4H, q,J=7.1Hz), 4.82(2H, s), 7.23–7.61(14H, m), 7.71(1H, d, J=7.3Hz), 8.31(1H,d, J=8.4Hz), 9.49(1H1, brs) 9-28

1.06(6H, d, J=6.9Hz), 1.20(6H, t, J=7.2Hz), 3.42–3.51(1H, m), 3.56(2H,s), 4.20(4H, q, J=7.2Hz, 4.85(2H, s), 7.28–7.77(15H, m), 8.72(1H, d,J=8.7Hz), 11.81(1H, brs) 9-29

0.49(3H, d, J=6.6Hz), 0.90(3H, d, J=6.6Hz), 1.14–1.25(6H, m),1.40–1.58(1H, m), 2.41(1H, d, J=3.6Hz), 3.51(2H, d, J=3.6Hz),3.81–3.88(1H, m), 4.02–4.18(4H, m), 4.83(2H, s), 6.79(1H, s),7.05–7.69(14H, m), 8.19(1H, d, J=8.1Hz), 9.01(1H, brs)

TABLE 65 Compound structure NMR(δ, 300MHz, CDCl₃) 2e)

2.86(3H, brs), 2.93(3H, brs), 3.56(2H, s), 7.09(1H, d, J=2.0Hz),7.23–7.71(9H, m), 8.29(1H, d, J=8.7Hz), 9.06(1H, brs). 2-17 e)

1.75–1.99(4H, m), 3.32–3.52(4H, m), 3.53(2H, s), 7.20–7.69(10H, m),8.22(1H, d, J=4.4Hz), 9.74(1H, brs).Formulation

Hereinafter, the present invention will be illustrated specifically byreferences of formulations.

Formulation 1

A film with a controlled thickness was prepared by use of a gelatinshell composition (a) in accordance with the conventional method. Twosheets of the film were inserted into a rotating left-right symmetricmetallic die rolls and molded into outer shells of soft capsules, whilea filling solution (b) was injected into the outer shells of the softcapsules, and simultaneously the outer shells of the softcapsules weremelted and sealed by the rotation of the die rolls, then the capsuleswere cut from the film. The capsules were dried in a rotary dryer, andallowed to dry for 4 days to give soft capsules. Hereinafter, specificexamples of formulations were given.

Formulation 1-1 (a) film composition gelatin 100 parts sugar alcoholsolution derived from corn starch  30 parts purified water 100 parts (b)filling solution (per capsule) propylene glycol fatty acid ester 295 mgethanol 105 mg

Formulation 1-2 (a) film composition gelatin 100 parts sugar alcoholsolution derived from corn starch  30 parts purified water 100 parts (b)filling solution (per capsule) compound of Example 2-5  5 mg propyleneglycol fatty acid ester 291 mg ethanol 104 mg

Formulation 1-3 (a) film composition gelatin 100 parts sugar alcoholsolution derived from corn starch  30 parts purified water 100 parts (b)filling solution (per capsule) compound of Example 2-5  5 mg propyleneglycol fatty acid ester 277 mg ethanol 148 mgFormulation 2

The compound of Example 2-22, an excipient and a binder were mixed in ausual method to prepare granulated powder. The powder obtained wasblended with a disintegrator and a lubricant to prepare a powder fortablets in a usual method. The powder was compressed to give tablets ina usual method. Specific examples of formulations were hereinaftergiven.

Formulation 2-1 compound of Example 2-22    5 mg lactose 133.06 mgcrystalline cellulose    18 mg hydroxypropyl methylcellulose 2910   5.4mg crospovidone    18 mg magnesium stearate  0.54 mg

Formulation 2-2 compound of Example 2-22    5 mg lactose 92.44 mg cornstarch   15 mg hydroxypropyl methylcellulose 2910  3.6 mg carboxymethylstarch  3.6 mg magnesium stearate  0.36 mg

Formulation 2-3 compound of Example 2-22    5 mg D-mannitol 158.4 mghydroxypropyl methylcellulose 2910    6 mg calcium silicate   20 mgcrospovidone   10 mg magnesium stearate  0.6 mgPharmacological Test

Test Example 1

Inhibition of Interliposomal Triglyceride (TG) Transfer Activity by MTP

Microsomal triglyceride transfer protein (MTP) from bovine liver waspartially purified in such a way described below. A buffer (50 mM Tris,250 mM sucrose, 1 mM EDTA, 0.02% NaN₃ (pH 7.4)) for making a homogenatepreparation was added to bovine liver, and the mixture was homogenatedunder ice-cooling, then centrifuged at 10,000×g (4° C., 30 minutes). Thesupernatant was adjusted to pH 5.1 with hydrochloric acid, and stirredfor 30 minutes. The solution was further centrifuged at 10,000×g (4° C.,30 minutes), and 1 mM Tris buffer was added to the precipitated residue,and the mixture was adjusted to pH 8.6 with sodium hydroxide. Afteraddition of 2.7M ammonium sulfate solution, the mixture was stirred for30 minutes, then centrifuged at 10,000×g (4° C., 40 minutes). Theresulting supernatant was served as a crude extraction fraction of MTPand stored at −80° C. under freezing. In its practical use, the crudeextraction fraction of MTP was purified by column chromatography ondiethylaminoethyl (DEAE) Sepharose using FPLC (Fast Performance LiquidChromatography) system, and the purified MTP was used for the test.

Small unilamellar-vesicle (SUV) liposome (donor, 0.25 mol % triolein, 5mol % cardiolipin) labeled with ¹⁴C-triolein and non-labeled SUVliposome (acceptor, 0.25 mol % triolein) were prepared. A fixed amountof donor and acceptor, and MTP were mixed with a sample dissolved inDMSO or with DMSO. The mixture was incubated in a 15 mM Trishydrochloride buffer (pH 7.4) containing 40 mM sodium chloride, 1 mMEDTA (ethylenediaminetetraacetic acid), 0.02% NaN₃ and 0.5% bovine serumalbumin at 37° C. for one hour. After completion of the incubation, asuspension of DEAE cellulose (50% v/v) in 15 mM Tris hydrochloridebuffer (pH 7.4) was added to the above solution, and the mixture wascentrifuged to separate the donor and the acceptor. The radioactivity inthe acceptor was measured by liquid scintillation counter. The valueobtained by subtracting the radioactivity in the blank from the amountof radioactivity in the acceptor of a DMSO group was determined asMTP-mediated TG transfer activity, and it was compared with the valueobtained by subtracting the radioactivity in the blank from theradioactivity in a sample group. The blank was prepared by adding 15 mMTris-HCl buffer (pH 7.4) in place of MTP. Inhibition rate (%) wascalculated from the values obtained according to the following equation.

Inhibition rate (%)=100×(1 minus ((radioactivity of sample group minusradioactivity of blank group)/(radioactivity of DMSO group minusradioactivity of blank group))).

50% Inhibition rate (IC₅₀) was determined on the basis of the aboveequation. The results were shown in Table 66 to 70.

Test Example 2

Inhibition of Apolipoprotein B Secretion from HepG2 Cells

HepG2 cells were suspended in Dulbecco's Modified Eagle's Medium (DMEM)(containing 10% fetal bovine serum, 100 units/mL penicillin and 100μg/mL streptomycin), and placed on a 96-well plate (4×10⁴ cells/well),then incubated for 24 hours. After removal of the medium, DMEM wasreplaced by a medium containing a sample dissolved in DMSO or a mediumcontaining DMSO (concentration of DMSO: 0.5%) and incubation was furtherperformed for 24 hours, after which the supernatant was recovered, andconcentration of apo B in the supernatant was assayed by Enzyme-LinkedImmunosorbent Assay (ELISA)

ELISA was carried out as follows. Anti-human apo B monoclonal antibody(0.5 μg/well) diluted with a solution of sodium carbonate in sodiumbicarbonate buffer (50 mL, pH 9.6) was placed in a 96-well plate forELISA, and allowed to stand at room temperature for 15 hours. Afterwashing the plate, a blocking solution (250 μL/well) was placed in thewell, and allowed to stand at room temperature for 1.5 hours. Afterwashing the plate, a standard and a sample (100 μL/well) were placed inthe well and allowed to stand at room temperature for one hour. Thestandard was prepared by adjusting the concentration of the purifiedhuman apo B with the DMEM to 0 to 1000 ng/mL. After washing the plate,an anti-human apo B polyclonal antibody labeled with a horse radishperoxidase which was diluted in 1:1000 with DEME (100 μL/well), andallowed to stand at room temperature for one hour. After washing theplate, 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) solution(100 μL/well) was placed in the well, and allowed to stand at roomtemperature for one hour. The reaction was stopped by addition of 2%oxalic acid (100 μL/well), and absorbency at 405 nm was measured.Concentration of apo B in the sample was calculated on the basis of astandard curve of the standard. Inhibition rate (%) was calculated fromthe assayed values in accordance with the following equation.

Inhibition rate (%)=100×(1 minus (concentration of apo B in samplegroup/concentration of apo B in DMSO group).

Based on the above equation, 50% inhibition concentration (IC₅₀) wasdetermined.

The results were shown in Tables 66 to 70.

TABLE 66 Test Example 2 Test Example 2 Test Example 1 Inhibition of TestExample 1 Inhibition of MTP inhibition apo B secretion MTP inhibitionapo B secretion Example IC₅₀ (nM) IC₅₀ (nM) Example IC₅₀ (nM) IC₅₀ (nM)1 0.6 5.8 1-2 42 850 1-3 4.7 5.75 1-4 3.4 190 1-5 0.66 0.65 1-6 1.2 5.51-7 7.55 330 1-8 37.5 720 1-9 5.95 3.2 1-11 32 22 1-12 7.6 63 1-13 5.8170 1-14 82 55 1-22 66.5 179.5 1-23 54 63 1-25 5 8.4 1-26 630 620 1-27 726 1-28 35 640 1-31 84.5 61 1-32 8.6 720 1-34 23 100 1-35 1.0 6.9 1-362.0 150 1-37 3.5 47 1-38 6.0 320 1-39 0.66 160 1-40 6.9 2.1 1-42 4.4 351-45 0.39 0.46 1-47 4.5 750 1-48 3.2 9.7 1-49 20 5.3 1-51 0.96 530 1-5210 690 1-53 0.43 860 1-62 5.0 46 1-63 16 90 1-66 16 9.3 1-67 27 28 1-699.1 90 1-70 1.6 270 1-71 1.8 120 1-72 0.44 2.7 1-73 — 39 1-74 — 680

TABLE 67 Test Example 2 Test Example 2 Test Example 1 Inhibition of TestExample 1 Inhibition of MTP inhibition apo B secretion MTP inhibitionapo B secretion Example IC₅₀ (nM) IC₅₀ (nM) Example IC₅₀ (nM) IC₅₀ (nM)1-75 — 97 1-76 — 120 1-77 — 360 1-78 — 11 1-79 — 0.59 1-80 — 8.2 1-81 —0.49 1-82 — 0.53 1-83 — 0.23 1-84 — 4.4 1-85 — 3.2 — — — 2 0.62 1.5 2-21.4 1.3 2-3 2.1 2.0 2-4 0.94 0.29 2-5 1.4 0.55 2-7 1.1 0.56 2-8 — 0.992-10 — 1.4 2-12 — 7.0 2-13 — 0.74 2-14 — 1.2 2-15 — 0.53 2-16 — 2.7 2-18— 0.69 2-19 — 26 2-20 — 0.64 2-21 1.8 8.9 2-22 1.4 0.44 2-23 2.7 0.612-24 — 28 2-25 — 6.3 2-26 — 8.2 2-29 — 91 2-30 — 27 2-31 — 43 2-32 — 1.72-33 — 13 2-34 — 2.0 2-35 — 38 2-36 — 7.4 2-39 0.74 0.76 2-40 — 0.992-41 — 1.2 2-42 — 1.8

TABLE 68 Test Example 2 Test Example 2 Test Example 1 Inhibition of TestExample 1 Inhibition of MTP inhibition apo B secretion MTP inhibitionapo B secretion Example IC₅₀ (nM) IC₅₀ (nM) Example IC₅₀ (nM) IC₅₀ (nM)2-43 — 9.0 2-44 — 33 2-45 — 39 2-46 — 2.9 2-47 — 1.2 2-48 — 0.36 2-49 —49 2-50 — 21 2-51 — 47 2-53 — 4.6 2-54 — 8.5 2-55 — 4.2 2-56 — 0.93 2-57— 0.56 2-58 — 1.9 2-59 — 0.99 2-60 — 1.3 2-61 — 0.38 2-62 — 0.37 2-66 —57 2-67 — 43 2-68 — 2.25 2-69 — 0.91 2-70 — 2.34 2-71 — 0.54 2-72 — 0.952-73 — 2.93 2-74 — 0.84 2-75 — 12.54 2-76 — 0.85 2-77 — 2.74 2-78 — 0.142-79 — 1.3 2-80 — 0.79 2-81 — 0.96 2-82 — 4.41 2-83 — 8.87 2-84 — 2.012-85 — 0.49 2-86 — 0.42 2-88 — 1.92 2-90 — 1.74 2-91 — 0.54 2-92 — 1.472-93 — 45.8 2-95 — 18

TABLE 69 Test Example 2 Test Example 2 Test Example 1 Inhibition of TestExample 1 Inhibition of MTP inhibition apo B secretion MTP inhibitionapo B secretion Example IC₅₀ (nM) IC₅₀ (nM) Example IC₅₀ (nM) IC₅₀ (nM)2-96 — 81 2-97 — 22 2-98 — 0.97 2-99 — 19 2-102 — 14.63 2-103 — 42.62-104 — 3.58 2-105 — 0.2 2-106 — 0.44 2-107 — 50 2-108 — 0.82 2-109 —0.93 2-110 — 0.65 2-114 — 3.1 2-115 — 44 2-117 — 38 2-118 — 49 — — — 3 —1.9 3-2 — 4.2 3-3 0.40 1.0 3-4 2.1 13 3-5 — 2.2 3-6 5.0 0.63 3-7 — 0.353-8 3.7 0.38 3-9 — 1.6 3-10 2.7 0.31 3-11 — 0.36 3-12 — 0.72 3-13 — 1.93-14 13 64 3-15 — 49.9 — — — 4 — 0.33 4-2 — 16 4-3 — 7.9 4-5 — 5.2 4-6 —7.5 4-7 — 15 4-8 — 10 — — — 5 3.1 19 5-2 66.5 875 5-3 6.2 86.5 5-4 2.457

TABLE 70 Test Example 2 Test Example 2 Test Example 1 Inhibition of TestExample 1 Inhibition of MTP inhibition apo B secretion MTP inhibitionapo B secretion Example IC₅₀ (nM) IC₅₀ (nM) Example IC₅₀ (nM) IC₅₀ (nM)5-5 4.5 5.0 5-6 3.9 260 5-8 14 340 5-9 4.0 28 5-10 6.2 300 5-11 1.3 5.15-12 — 1.3 5-13 — 2.4 5-14 — 0.34 5-15 — 6.4 5-16 — 3.0 5-17 — 5.2 63.47 58.3 6-3 5.2 510 6-8 50 630 6-10 22 870 6-14 6.3 87 6-15 2.0 576-16 2.9 170 6-17 2.3 420 6-19 3.2 35 6-21 9.8 920 7 4.97 60.0 7-2 2.4626 7-5 16.2 237 — — — 8 33 595 — — — 9 11 260 9-2 4.2 450 9-3 — 59 9-4 —9.9 9-5 — 3.1 9-6 — 59 9-8 — 6.9 9-10 — 2.3 9-11 20 210 9-13 — 0.53 9-14— 41 9-17 — 23 9-21 — 20 9-22 — 0.96 9-23 — 8.77 9-24 — 7.86 9-27 — 0.82— — —

Test Example 3

Olive Oil-Loading Test

Syrian hamsters (9-11 weeks of age) under non-fasted conditions wereused in the test. Blood was collected previously from orbital venousplexus, and a sample was suspended in 0.5% methyl cellulose (vehicle)and the suspension was forced to be administered orally to the hamstersat a dose of 0.3, 1, 3 or 10 mg/2 mL/kg. Only vehicle in the same volumewas administered to the control group. Olive oil (2 mL/kg) was forced tobe administered orally 30 minutes after the administration of thesample, and blood was collected from orbital venous plexus 4 hourslater. Plasma was recovered from the blood, and the amount oftriglyceride (TG) in the plasma was determined by automatic analyzer(Hitachi Co.). The data was expressed in terms of ΔTG(mg/dL)=the valueat 4^(th) hr minus the value before administration. Inhibition rate (%)was calculated from the data obtained on the basis of the followingequation.

Inhibition rate (%)=100×(1 minus ΔTG of sample group/ΔTG of controlgroup). The results were shown in Table 71.

TABLE 71 Test Example 3 Test Example 3 Inhibition of fat Inhibition offat absorption after absorption after olive oil-loading in oliveoil-loading in Hamster (( )mg/kg.p.o) Hamster (( )mg/kg.p.o) ExampleInhibition rate (%) Example Inhibition rate (%) 1  57(100) 1-3  65(100)1-5 59(3) 1-6  54(10) 1-35  59(100) 1-45  71(100) 1-66  52(100) 1-72 54(100) 2  95(10) 2-2  96(10) 2-3 68(3) 2-4 78(3) 2-5 70(3) 2-7 58(3)2-8 89(3) 2-13 70(3) 2-14 80(3) 2-15 81(3) 2-18 58(3) 2-22 61(3) 2-2555(3) 2-39 68(3) 2-48 87(3) — — 3-3  78(10) 3-5  80(10) 3-6 52(3) 3-774(3) 3-8 60(3) 3-10 85(3) 3-11 75(3) — — 5-9  78(100) 5-11  64(100)9-10 54(3) 9-13 70(3)

Test Example 4

Liver TG Release Inhibition Test

Syrian hamsters (9 to 11 weeks of age) which were fasted for one daywere used in the test. Blood was collected previously from orbitalvenous plexus, and a sample was forced to be administered orally to thehamsters at a dose of 30, 100 or 300 mg/2 mL/kg, and the same amount ofvehicle was administered to the control group. Triton WR 1339 (2 mL/kg)was intravenously administered to the hamsters 30 minutes after theabove administration. Two hours later, blood was collected from orbitalvenous plexus, and plasma was separated from the blood. The amount of TGin the plasma was determined by automatic analyzer (Hitachi Co.). Thedata was expressed in terms of TG release velocity (mg/dL/min)=(value at2^(nd) hour minus value before administration)/120. Inhibition rate (%)was calculated from the data obtained on the basis of the followingequation.

Inhibition rate (%)=100×(1 minus TG release velocity of sample/TGrelease velocity of control group). The results were shown in Table 72.

TABLE 72 Test Example 4 Test Example 4 Inhibition of liver TG Inhibitionof liver TG release in Hamster release in Hamster Example (( )mg/kg.p.o)Example (( )mg/kg.p.o) No. Inhibition rate(%) No. Inhibition rate(%) 119(300) 1-6 0(100) 1-35  9(300) 2-5 0(100) 2-22 0(30) 2-39 6(100) 3-318(100) — —

Test Example 5

Combination Use Test

Japanese white rabbits (male, 19 weeks of age, JW, purchased fromKitayama Labes Co., Ltd.) were fed previously in such a way that theywere fed a high cholesterol diet (0.3% cholesterol+3% peanut oil-addedRC-4, Product of Oriental Yeast Co., Ltd.) of 70 g/day under limitedfeeding for one day. The rabbits thus fed were used as acholesterol-loaded rabbit model, and the grouping of such model wascarried out in such a way that there might be no variation in the amountof plasma cholesterol among each group (five rabbits/group). Aftercollection of blood from auricular artery, compounds of Examples 2 to 5,simvastatin, and compounds of Examples 2 to 5 plus simvastatin wereadded to a high cholesterol diet in the dose as shown in Table below,and the rabbits were fed such diet. The rabbits were fed 70 g of eachdiet every morning. Blood was collected from auricular artery 6 hoursafter the feeding on the 4^(th) day of the administration, andcholesterol level in plasma was assayed. In the table, increased amountof plasma cholesterol during from the time of grouping to the 4^(th) daywas shown.

TABLE 73 Increased amount of total cholesterol (mg/dl) Control 80.0Simvastatin (1 mg/kg) 48.6 Example 2-5 (10 mg/kg) 8.6 Example 2-5 (10mg/kg) + 2.1 Simvastatin (1 mg/kg)

Test Example 6

Determination of the Concentration in Plasma

Syrian hamsters (9-15 weeks of age) under non-fasted conditions wereused in the test. A sample was suspended in 0.5% methyl cellulose(vehicle), and the suspension was forced to be administered orally tothe hamsters at a dose of 30 or 100 mg/2 mL/kg. After a fixed period oftime, blood was partly collected from orbital venous plexus, and thehamsters were subjected to laparotomy under ether anesthesia, and thenblood was collected from portal vein. The blood was immediately cooledwith ice to separate plasma. A portion of the plasma was extracted withan organic solvent and the supernatant was recovered. Concentration ofthe sample (unchanged form) and that of the metabolite in thesupernatant were determined quantitatively by high performance liquidchromatography/mass spectrometry (LC/MS) comparing with chromatogram ofsynthetic standard.

TABLE 74 Blood of portal Peripheral blood vein (μM) (μM) Compound Dose(mg/kg) Component 1 h 2 h 4 h 1 h 2 h 4 h 1-2  30 Unaltered form <0.2<0.2 <0.2 <0.2 <0.2 <0.2 Metabolite 1.6 2.2 6.7 0.9 1.3 2.9 1-12 30Unaltered form <0.2 <0.2 <0.2 <0.2 <0.2 <0.2 Metabolite 11.8 18.2 24.47.3 12.1 15.4 1-13 30 Unaltered form <0.2 <0.2 <0.2 <0.2 <0.2 <0.2Metabolite 11.8 20.6 27.3 10.9 16.9 18.3 2-5  30 Unaltered form 0.010.03 0.01 <0.02 <0.02 <0.02 Metabolite 0.33 0.73 0.38 0.01 0.01 0.02

Test Example 7

Metabolic Stability Test in Liver S9 and Small Intestine S9

Human and hamster liver S9 (final concentration: 2 mg protein/mL), andhuman and hamster small intestine S9 (final concentration: 2 mgprotein/mL) were each suspended in 100 mM potassium phosphate buffer (pH7.4, containing β-nicotinamide adenine dinucleotide phosphate: 1.3 mM,D-glucose-6-phosphate: 3.3 mM, magnesium chloride: 3.3 mM,glucose-6-phosphate dehydrogenase: 0.4 U/mL). The suspensions were mixedwith a solution of a sample (Example 2-5) in DMSO. The solutions wereincubated at 37° C. for 0, 10 and 60 minutes, and an organic solvent wasadded thereto. The solutions were centrifuged, and the concentration ofthe sample (unchanged form) in the supernatant was determined by highperformance liquid chromatography/mass spectrometry (LC/MS). Based onthe data obtained, remaining rate (%) was calculated according to thefollowing equation.

Remaining rate(%)=amount of sample 10 or 60 minutes afterincubation/amount of sample at zero time after incubation×100

TABLE 75 human hamster Remaining Remaining Remaining Remaining rate (%)rate (%) rate (%) rate (%) after 10 min. after 60 min. after 10 min.after 60 min. Small intestine 97.6 91.5 29.0 14.1 S9 Liver S9 7.9 4.32.4 0

Test Example 8

Inhibitory Activity on MTP and apo B Secretion Inhibition by Metabolites

In a similar manner to Test Examples 1 and 2, the activity ofmetabolites was assayed. The results were shown in Table below.

TABLE 76 MTP Inhibition of inhibition apo B secretion Compound Mainmetabolite IC₅₀ (nM) IC₅₀ (nM) 1

>1000 >10000

>1000 >10000 1-35

>1000 >10000

>1000 >10000

TABLE 77 MTP Inhibition of inhibition apo B secretion Compound Mainmetabolite IC₅₀ (nM) IC₅₀ (nM) 2-5

>10000 >10000

>1000 >10000 2-17

— >10000

>1000 >10000

TABLE 78 MTP Inhibition of inhibition apo B secretion Compound Mainmetabolite IC₅₀ (nM) IC₅₀ (nM) 3-4

>1000 >10000

>1000 >10000

INDUSTRIAL APPLICABILITY

It is apparent from the above Test Examples 1 to 3 that novel compoundsand their pharmaceutically acceptable salts of the present inventionpossess excellent MTP inhibition activity and also strongly inhibitabsorption of triglyceride. In addition, as is apparent from TestExample 4, even when compounds of the present invention are administeredat high dose, inhibition rate of liver TG release is 18-19% or lower,more effectively 9% or lower, especially effectively 0% or lower, andthus the compounds of the present invention inhibit little of liver TGrelease. Further, Test Example 6 reveals that active compounds afterabsorption in the small intestine are present in portal vein in a verysmall amount, and since most (8-fold to 80-fold amount) of such activecompounds are metabolites, they do not reach the liver. Furthermore, itis deduced from Test Example 7 that a small amount of active compoundwhich has reached the liver is metabolized rapidly to a metabolite. Inaddition, Test Example 8 proves that ester moiety of these metabolitesis cleaved by hydrolysis and thus they have little or no MTP inhibitoryactivity. Further, Test Example 5 reveals that combination use of thecompounds of the present invention with other agents for treatinghyperlipidemia (statin type agents) can remarkably inhibit the increaseof cholesterol and exhibit extremely excellent synergistic effect. Thesefacts elucidate that the compounds of the present invention can be usedin combination with other agents, particularly other agents for treatinghyperlipidemia, arteriosclerosis, coronary artery diseases, obesity,diabetes or hypertension.

From the fact as mentioned above, it is understood that novel compoundsof the present invention and their pharmaceutically acceptable salts caninhibit lipid absorption in the small intestine and further do notinhibit TG release in the liver. This means that the compounds of thisinvention do not inhibit MTP in the liver, but selectively inhibit MTPin the small intestine.

Therefore, selective inhibition of MTP activity in the small intestineby the compounds of the present invention should lower lipid absorption,which makes it possible to control lipoproteins such as triglyceride,cholesterol and LDL, etc. in blood or to control lipid in cells.Further, since the compounds of the present invention do not affectliver MTP, accumulation of triglyceride does not occur in the liver.Consequently, inhibition of fatty liver generation as an adverse effectmight be expected. Therefore, the compounds of the present invention canbe said novel MTP inhibitors having no side effects such as a fattyliver, etc. or, in other words, they are novel agents for the treatmentor prophylaxis of hyperlipidemia, arteriosclerosis, coronary arterydiseases, obesity, diabetes or hypertension, and further for thetreatment or prophylaxis of pancreatitis, hypercholesterolemia,hypertriglyceridemia, etc., which rarely act on MTP in the liver and dosubstantially inhibit only MTP in the small intestine.

1. An ester compound represented by the formula (1′)

wherein R^(2′) and R^(2″) are each independently hydrogen, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, halogen, halo C₁-C₆ alkyl, C₁-C₆ acyl,C₂-C₆ alkenyl, or cyano; X₁ is —O— or —NR¹⁰— wherein R¹⁰ is hydrogen,C₁-C₆ alkyl, or C₃-C₇ cycloalkyl; R¹ is hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆ alkyloxy,optionally substituted C₆-C₁₄ aryl, optionally substituted C₇-C₁₆aralkyl, optionally substituted C₆-C₁₄ aryloxy, optionally substitutedC₇-C₁₆ aralkyloxy, optionally substituted C₇-C₁₅ arylcarbonyl, C₂-C₇alkoxycarbonyl, halogen, C₂-C₆ alkenyl, —N(R⁴⁰)(R⁴¹) wherein R⁴⁰ and R⁴¹are each independently hydrogen or optionally substituted C₆-C₁₄ aryl,R³ and R⁴ are each independently hydrogen, hydroxy, halogen, optionallysubstituted C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkyl, C₇-C₁₆aralkyloxy, C₁-C₆ acyl, CON(R¹¹ )(R¹²) (wherein R¹¹ and R¹² are eachindependently hydrogen, C₁-C₆ alkyl, optionally substituted C₆-C₁₄ aryl,optionally substituted C₇-C₁₆ aralkyl, or C₁-C₆ alkoxy),—(CH₂)_(g)—N(R¹³)(R¹⁴) (wherein R¹³ and R¹⁴ are each independentlyhydrogen, C₁-C₆ alkyl, C₂-C₇ alkoxycarbonyl, or C₁-C₆ acyl, and q is aninteger of 0 to 3), or —CO(R¹⁵) (wherein R¹⁵ is hydroxy, C₁-C₆ alkoxy,optionally substituted C₆-C₁₄ aryloxy, optionally substituted C₇-C₁₆aralkyloxy or C₁-C₆ alkyl); l is an integer of 0 to 3; m is an integerof 0 to 3; R⁵, R⁶, and R⁷ are each independently hydrogen C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₇ alkoxycarbonyl, carboxyl, halogen, cyano, nitro,halo C₁-C₆ alkyl, C₁-C₆ acyl, hydroxy, amino, optionally substitutedC₆-C₁₄ aryl, or —(CH₂)_(r)—CON(R¹⁶)(R¹⁷) (wherein R¹⁶ and R¹⁷ are eachindependently hydrogen, C₁-C₆ alkyl, or halo C₁-C₆ alkyl and r is aninteger of 0 to 3); ring C is C₆-C₁₄ aryl, C₇-C₁₅ arylcarbonylamino,C₈-C₁₇ aralkylcarbonylamino, C₃-C₇ cycloalkyl, or C₇-C₁₆ aralkyl, orring C may be taken together with R⁷ and R⁸ to form

R⁸ and R⁹ are each independently hydrogen, C₁-C₆ alkyl, optionallysubstituted C₆-C₁₄ aryl, hydroxy C₁-C₆ alkyl, —CON(R¹⁸)(R¹⁹) (whereinR¹⁸ and R¹⁹ are each independently hydrogen, C₁-C₆ alkyl, C₃-C₇cycloalkyl, halo C₁-C₆ alkyl, C₂-C₁₂ alkoxyalkyl, or optionallysubstituted C₆-C₁₄ aryl), —COO(R²⁰), or —(CH₂)_(s)—OCO(R²⁰) (wherein R²⁰is hydrogen, C₁-C₆ alkyl, or C₃-C₇ cycloalkyl, s is an integer of 0 to3), —N(R²¹ )(R²²) (wherein R²¹ and R²² are each independently hydrogen,C₁-C₆ alkyl, C₁-C₆ acyl, or C₁-C₆ alkylsulfonyl), or R⁸ and R⁹ may betaken together to form C₃-C₇ cycloalkyl, or a pharmaceuticallyacceptable salt thereof.
 2. The ester compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein the ring C is

in which q is an integer of 0 to
 3. 3. The ester compound or apharmaceutically acceptable salt thereof according to claim 2, whereinX₁ is —NR¹⁰—.
 4. The ester compound or a pharmaceutically acceptablesalt thereof according to claim 2, wherein X₁ is —O—.
 5. The estercompound or a pharmaceutically acceptable salt thereof according toclaim 1, wherein the group —(CH₂)_(l)— is located at the h-position ofthe benzene ring in the formula (1′).
 6. The ester compound or apharmaceutically acceptable salt thereof according to claim 1, whereinthe group —(CH₂)_(l)— is located at the i-position of the benzene ringin the formula (1′).
 7. The ester compound or a pharmaceuticallyacceptable salt thereof according to claim 1, wherein R⁸ and R⁹ are each—CON(R¹⁸)(R¹⁹)— or R⁸ and R⁹ are each —COO(R²⁰)—.
 8. The ester compoundor a pharmaceutically acceptable salt thereof according to claim 3,wherein the ring C is


9. The ester compound or a pharmaceutically acceptable salt thereofaccording to claim 8, wherein ring C is phenyl.
 10. The ester compoundor a pharmaceutically acceptable salt thereof according to claim 3,wherein the ring C is

and q is an integer of 0 to
 3. 11. An ester compound or apharmaceutically acceptable salt thereof, which is selected from thegroup consisting of2-(2-{3-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diisopropyl ester,2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid dimethyl ester,2-cyclophentyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid dicyclohexyl ester,2-benzyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-(2-{2-methyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-cyclohexyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-phenyl-2-(2-{2-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-phenyl-2-(2-{3-trifluoromethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-(2-{4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(4′-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-phenyl-2-(2-{4-[(3′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-(2-{4-[isopropyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[cyclohexyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid dipropyl ester,2-phenyl-2-(2-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diisobutyl ester,2-(2-{4-[ethyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-ethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-isopropyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-isobutyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-bromo-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-diethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-diisopropylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-(ethyl-methylcarbamoyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-[2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-fluoro-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(4′-bromo-biphenyl-2-carbonyl)-amino]}-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-[dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid dimethyl ester,2-cyclopentyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-cyclohexyl-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonicacid diethyl ester,2-(2-{4-[(4′-chloro-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(4′-acetyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(4′-cyano-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-[3-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-propyl]-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(5-methoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(2′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-bromo-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-chloro-5-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(3′-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(3′-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-o-tolyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-m-tolyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-p-tolyl-malonicacid diethyl ester,2-(2-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic acid diethyl ester,2-(3-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic acid diethyl ester,2-(4-chloro-phenyl)-2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-malonic acid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-succinicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(2-methoxy-phenyl)-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(3-methoxy-phenyl)-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-(4-methoxy-phenyl)-malonicacid diethyl ester,2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(6-fluoro-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-[2-(2-{3-dimethylcarbamoyl-4-[(5-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxy)-ethyl]-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(5-ethoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(5-isopropoxy-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-[2-(2-{4-[(5,4′-bis-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3-dimethylcarbamoyl-phenyl}-acetoxy)-ethyl)]-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-(6-methoxy-4′-trifluoro-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-(3-methyl-4′-trifluoro-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-ethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropenyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylcarbamoyl-4-[(4′-isopropyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-ethoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-methoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-isopropoxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{2-chloro-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzoyloxy}-ethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-ethoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(3-{3-dimethylcarbamoyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-propionyloxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-benzyloxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-carboxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-isopropoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-methoxycarbonyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-acetylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-methoxycarbonylamino-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-phenyl-2-(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-biphenyl-3-yl}-acetoxymethyl)-malonicacid diethyl ester,2-(2-{3-formyl-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-dimethylaminomethyl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-(methoxy-methylcarbamoyl)-4-[(4′-trifluoro-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester,2-(2-{3-isobutyryl-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester, and2-(2-{3-(1-hydroxy-2-methyl-propyl)-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-acetoxymethyl)-2-phenyl-malonicacid diethyl ester.
 12. An ester compound according to the followingstructural formula:

or a pharmaceutically acceptable salt thereof.
 13. An ester compoundaccording to the following structural formula:

or a pharmaceutically acceptable salt thereof.
 14. An ester compoundaccording to the following structural formula:

or a pharmaceutically acceptable salt thereof.
 15. An ester compoundaccording to the following structural formula:

or a pharmaceutically acceptable salt thereof.
 16. An ester compoundaccording to the following structural formula:

or a pharmaceutically acceptable salt thereof.
 17. An ester compoundaccording to the following structural formula:

or a pharmaceutically acceptable salt thereof.
 18. An ester compoundaccording to the following structural formula:

or a pharmaceutically acceptable salt thereof.
 19. A method for treatinghyperlipidemia, comprising administering to a subject in need thereof,the ester compound according to any one of claims 1-7, 8-10, 11, 12-17,or 18, or a pharmaceutically acceptable salt thereof.
 20. A method fortreating arteriosclerosis, comprising administering to a subject in needthereof, the ester compound according to any one of claims 1-7, 8-10,11, 12-17, or 18, or a pharmaceutically acceptable salt thereof.
 21. Amethod for treating a coronary artery disease, comprising administeringto a subject in need thereof, the ester compound according to any one ofclaims 1-7, 8-10, 11, 12-17, or 18, or a pharmaceutically acceptablesalt thereof.
 22. A method for treating obesity, comprisingadministering to a subject in need thereof, the ester compound accordingto any one of claims 1-7, 8-10, 11, 12-17, or 18, or a pharmaceuticallyacceptable salt thereof.
 23. A method for treating diabetes, comprisingadministering to a subject in need thereof, the ester compound accordingto any one of claims 1-7, 8-10, 11, 12-17, or 18, or a pharmaceuticallyacceptable salt thereof.
 24. A method for treating hypertension,comprising administering to a subject in need thereof, the estercompound according to any one of claims 1-7, 8-10, 11, 12-17, or 18, ora pharmaceutically acceptable salt thereof.
 25. The method according toclaim 19, further comprising administering one or more additionalantihyperlipidemic drugs.
 26. The method according to claim 25 whereinthe additional antihyperlipidemic drug is a statin-type drug.
 27. Themethod according to claim 26 wherein the statin-type drug is selectedfrom lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,and cerivastatin.
 28. The method according to claim 22, furthercomprising administering one or more additional drugs that are usefulfor the treatment of obesity.
 29. The method according to claim 28wherein the additional drug is selected from mazindol and orlistat. 30.The method according to claim 22, further comprising administering oneor more additional drugs that are useful for the treatment of diabetes.31. The method according to claim 30, wherein the additional drug isselected from insulin preparations, sulfonylurea drugs, insulinsecretagogues, sulfonamide drugs, biguanide drugs, α-glucosidaseinhibitors, and insulin resistance improving drugs.
 32. The methodaccording to claim 30, wherein the additional drug is selected frominsulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide,glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metforminhydrochloride, buformin hydrochloride, boglibose, acarbose, andpioglitazone hydrochloride.
 33. The method according to claim 24,further comprising administering one or more additional drugs that areuseful for the treatment of hypertension.
 34. The method according toclaim 33, wherein the additional drug is selected from loop diuretics,angiotension converting enzyme inhibitors, angiotension II receptorantagonists, calcium antagonists, beta-blockers, alpha/beta blockers,and alpha blockers.
 35. The method according to claim 33, wherein theadditional drug is selected from furosemide delayed release, captopril,captopril delayed release, enatapril maleate, alacepril, delaprilhydrochloride, silazapril, lisinopril, benazepril hydrochloride,imidapril hydrochloride, temocapril hydrochloride, quinaprilhydrochloride, trandolapril, perindopril erbumine, losartan potassium,candesartan cilexetil, nicardipine hydrochloride, nicardipinehydrochloride delayed release, nilvadipine, nifedipine, nifedipinedelayed release, benidipine hydrochloride, diltiazem hydrochloride,diltiazem hydrochloride delayed release, nisoldipine, nitrendipine,manidipine hydrochloride, barnidipine hydrochloride, efonidipinehydrochloride, amlodipine besylate, felodipine, cilnidipine,aranidipine, propranolol hydrochloride, propranolol hydrochloridedelayed release, pindolol, pindolol delayed release, indenololhydrochloride, carteolol hydrochloride, carteolol hydrochloride delayedrelease, bunitrolol hydrochloride, bunitrolol hydrochloride delayedrelease, atenolol, asebutolol hydrochloride, metoprolol tartrate,metoprolol tartrate delayed release, nipradilol, penbutolol sulfate,tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxololhydrochloride, celiprolol hydrochloride, bopindolol malonate, bevantololhydrochloride, labetalol hydrochloride, arotinolol hydrochloride,amosulalol hydrochloride, prazosin hydrochloride, terazosinhydrochloride, doxazosin mesylate, bunazocin hydrochloride, bunazocinhydrochloride delayed release, urapidil, and phentolamine mesylate. 36.An MTP (microsomal triglyceride transfer protein) inhibitor, comprising,as an active ingredient, the ester compound of any one of claims 1-7,8-10, 11, 12-17, or 18, or a pharmaceutically acceptable salt thereof.37. A pharmaceutical composition, which comprises the ester compound ofany one of claims 1-7, 8-10, 11, 12-17, or 18, or a pharmacueticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.